CN103012304A - Compounds for preparing immunological adjuvant - Google Patents
Compounds for preparing immunological adjuvant Download PDFInfo
- Publication number
- CN103012304A CN103012304A CN2012103581411A CN201210358141A CN103012304A CN 103012304 A CN103012304 A CN 103012304A CN 2012103581411 A CN2012103581411 A CN 2012103581411A CN 201210358141 A CN201210358141 A CN 201210358141A CN 103012304 A CN103012304 A CN 103012304A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- group
- reaction
- heptane
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title abstract description 86
- 239000000568 immunological adjuvant Substances 0.000 title abstract description 9
- 239000013078 crystal Substances 0.000 claims abstract description 27
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 4
- 125000006850 spacer group Chemical group 0.000 claims description 3
- -1 (R-4,5-dihydro-2-phenyloxazol-4-yl)methoxy Chemical group 0.000 abstract description 89
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 144
- 238000006243 chemical reaction Methods 0.000 description 86
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 80
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 74
- 239000001257 hydrogen Substances 0.000 description 70
- 229910052739 hydrogen Inorganic materials 0.000 description 70
- 239000000243 solution Substances 0.000 description 63
- 239000011541 reaction mixture Substances 0.000 description 62
- 125000000217 alkyl group Chemical group 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 50
- 238000002360 preparation method Methods 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 48
- 239000010410 layer Substances 0.000 description 44
- 238000000034 method Methods 0.000 description 44
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- 238000003756 stirring Methods 0.000 description 41
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 40
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- 239000000203 mixture Substances 0.000 description 33
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- 125000000304 alkynyl group Chemical group 0.000 description 31
- 229910052757 nitrogen Inorganic materials 0.000 description 31
- 125000003118 aryl group Chemical group 0.000 description 30
- 125000001931 aliphatic group Chemical group 0.000 description 28
- 238000004809 thin layer chromatography Methods 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
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- 238000005406 washing Methods 0.000 description 26
- 229910052799 carbon Inorganic materials 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
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- 125000000623 heterocyclic group Chemical group 0.000 description 15
- 239000012266 salt solution Substances 0.000 description 15
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 14
- 239000000543 intermediate Substances 0.000 description 14
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- 229920006395 saturated elastomer Polymers 0.000 description 13
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- 238000011010 flushing procedure Methods 0.000 description 10
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 10
- NRTYMEPCRDJMPZ-UHFFFAOYSA-N pyridine;2,2,2-trifluoroacetic acid Chemical compound C1=CC=NC=C1.OC(=O)C(F)(F)F NRTYMEPCRDJMPZ-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 150000002431 hydrogen Chemical class 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 8
- XLKOZYOVXNPWGT-UHFFFAOYSA-N 3-oxotetradecanoic acid Chemical class CCCCCCCCCCCC(=O)CC(O)=O XLKOZYOVXNPWGT-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
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- 229960005486 vaccine Drugs 0.000 description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 7
- 230000003213 activating effect Effects 0.000 description 7
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- 230000009466 transformation Effects 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
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- 125000004429 atom Chemical group 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- 235000014493 Crataegus Nutrition 0.000 description 5
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- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- KTQKOGBTMNDCFG-UHFFFAOYSA-N tert-butyl(diphenyl)silicon Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)C1=CC=CC=C1 KTQKOGBTMNDCFG-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- QXZGXRIXJAVMTI-UHFFFAOYSA-N tribenzylsilicon Chemical compound C=1C=CC=CC=1C[Si](CC=1C=CC=CC=1)CC1=CC=CC=C1 QXZGXRIXJAVMTI-UHFFFAOYSA-N 0.000 description 1
- QXTIBZLKQPJVII-UHFFFAOYSA-N triethylsilicon Chemical compound CC[Si](CC)CC QXTIBZLKQPJVII-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940124856 vaccine component Drugs 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
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Abstract
The invention provides compounds for preparing an immunological adjuvant, and especially the invention provides a crystal ER-806158, (R)-1-(((R-4,5-dihydro-2-phenyloxazol-4-yl)methoxy)decyl-3-ol which has a triclinic system and a P1space group.
Description
The application is that application number is 200680023963.7, and the applying date is on June 30th, 2006, and denomination of invention is divided an application for the Chinese patent application of " for the preparation of the compound of immunological adjuvant ".
Technical field
The present invention relates to the compound for the preparation of immunological adjuvant.
Background technology
Proved that vaccine normally is used for the method for the success that keeps off infection.Generally speaking, it is that cost is effective, and can not induce the antibiotics resistance of target pathogenic agent or impact to be present in normal microflora among the host.In a lot of situations, for example when the immunity of inducing anti-disease poison, vaccine can prevent not have the disease of feasible healing or the property improved methods for the treatment of.
Vaccine works to replying of medicament or antigen to cause by activating immune system, normally is incorporated into communicable organism or its part in the body with noninfectious or non-pathogenic form.In case immunity system is to described organism and Yan Yishi " waits to send out " or " activation ", this organism that immunity system is exposed to as the infectivity cause of disease produces quick and strong immunne response, and described immunne response can be bred in host organisms and infects enough cells and destroy cause of disease with before causing illness in cause of disease.
Being used for the medicament of activating immune system or antigen can be the complete organism that is in weak infectivity state, being called the attenuated organism body, perhaps is carbohydrate, protein or peptide that the component of organism for example represents the various structural constituents of organism in some cases.
In many cases, for stimulating immune system is enough to make vaccine effective, namely immunize, be necessary to strengthen to being present in the immunne response of the antigen in the vaccine.Numerous protein and most of peptide and Carbohydrate Antigens are not used separately and can be caused the antibody response that is enough to immunize.Need such antigen can be considered to external and can cause that the mode of immunne response offers immunity system with it.For this reason, designed the additive (adjuvant) that immobilized antigen and immune stimulatory are replied.
Foremost adjuvant, Freund's complete adjuvant is by the compositions of mixtures of the mycobacterium in oil/water emulsion.Freund's adjuvant works by dual mode: the first, by improving cell and humoral mediated immunity, the second is by stoping the rapid dispersion (" storage effect ") of antigen stimulation.Yet owing to physiology and the immune response of poisoning frequently to this material, freund's adjuvant can not be used for human.
The another kind of molecule with Immunestimulatory effect or adjuvanticity that shown is intracellular toxin, is also referred to as lipopolysaccharides (LPS).LPS is by bringing out " inborn " immunne response, namely developed into so that organism can identify intracellular toxin (with the invasion bacterium, wherein intracellular toxin be the invasion bacterium integral part) reply, come stimulating immune system, and do not need to contact with organism in advance.Can not be as feasible adjuvant although LPS toxicity is too large, structurally the molecule relevant with intracellular toxin for example monophosphoryl lipid A (" MPL ") just carry out test as adjuvant in clinical trial.Confirmed that LPS and MPL are people toll sample acceptors-4 (TLR-4).Yet at present unique adjuvant that is used for the mankind of being approved by FDA is aluminium salt (alum), and it is used for by the precipitation of antigen " storage " antigen.Alum also stimulates the immunne response to antigen.
Therefore, for stimulating immune system to produce more independent than antigen or the viewed stronger antibody response for antigen when injecting with alum, need exploitation for the preparation of the synthetic method of the compound that can use altogether with antigen.
Summary of the invention
On the one hand, the invention provides the method for a kind of TLR-4 receptor stimulant E6020 for the synthesis of having following structure:
On the other hand, the present invention includes method for the synthesis of any steric isomer of E6020.Therefore, be provided for preparing the synthetic intermediate of the compound with following structure at this:
When for example vaccine was applied to bacillary and virus disease altogether with antigen, these compounds can be used as immunological adjuvant.The present invention also provides the synthetic intermediate that can be used for preparing E6020 and steric isomer thereof.
The invention still further relates to following aspect:
1. the compound or its salt of formula (15):
Wherein:
A is-(CH
2)
x-O-or covalent linkage;
N is 0 or 1;
X is 1~6;
R
1aHydrogen, C
1~C
6Alkyl, C
3~C
6Thiazolinyl, C
3~C
6Alkynyl or phosphorous acid ester oxygen protecting group or phosphoric acid ester oxygen protecting group;
R
2aAnd R
2bOne of be H, another is the monovalence nitrogen-protecting group; Perhaps R
2aAnd R
2bThe divalence nitrogen-protecting group together;
When A is-(CH
2)
xDuring-O-, R
3aAnd R
3bOne of be H, another is monovalence nitrogen-protecting group, perhaps R
3aAnd R
3bThe divalence nitrogen-protecting group together;
When A is covalent linkage, R
3aAnd R
3bC
1~C
6Alkyl, perhaps R
3aAnd R
3bBe together-(CH
2)
4-,-(CH
2)
5-or-(CH
2)
2O (CH
2)
2-;
R
4C
5~C
12Alkyl or C
5~C
12Thiazolinyl; And
R
5C
5~C
15Alkyl or C
5~C
15Thiazolinyl.
2. such as project 1 described compound, wherein R
2aAnd R
2bOr R
3aAnd R
3bDescribed nitrogen-protecting group be independently selected from Boc, Fmoc, TROC, TMS-ethyl carbonyl, cyanoethyl carbonyl, allyloxy carbonyl, (C
6H
5)
2C=, monoethyl diamide or trinitride.
3. such as project 1 described compound, wherein with R
2aAnd R
2bProtecting group on the described nitrogen that connects can remove under the first condition that is selected from acidity, alkalescence, oxidation and reductive condition; And with R
3aAnd R
3bProtecting group on the described nitrogen that connects can remove under the second condition that is selected from its excess-three kind condition that is different from described first condition.
4. such as project 1 described compound, wherein A is-(CH
2)
2-O-; N is 0; R
4C
7Alkyl; And R
5C
11Alkyl.
5. such as project 4 described compounds, it has formula ER-820842:
6. such as project 1 described compound, wherein A is-(CH
2)
2-O-; N is 1; R
4C
7Alkyl; And R
5C
11Alkyl.
7. such as project 6 described compounds, it has formula ER-819344:
8. such as project 1 described compound, wherein A is covalent linkage; N is 0; R
4C
7Alkyl; And R
5C
11Alkyl.
9. such as project 8 described compounds, it has formula ER-819385:
10. such as project 1 described compound, wherein A is covalent linkage; N is 0; R
3aAnd R
3bEach is sec.-propyl naturally; R
4C
7Alkyl; And R
5C
11Alkyl.
11. such as project 10 described compounds, it has formula ER-820116:
12. such as project 1 described compound, wherein A is-(CH
2)
2-O-; N is 0; R
4C
7Alkyl; And R
5C
11Alkyl.
13. the compound or its salt of formula (16):
Wherein:
N is 0 or 1;
R
1aHydrogen, C
1~C
6Alkyl, C
3~C
6Thiazolinyl, C
3~C
6Alkynyl, phosphorous acid ester oxygen protecting group or phosphoric acid ester oxygen protecting group;
R
2aAnd R
2cOne of be H, another be the monovalence nitrogen-protecting group or-C (O) CH
2C (O) R
6R
2aAnd R
2cThe divalence nitrogen-protecting group together;
R
4C
5~C
12Alkyl or C
5~C
12Thiazolinyl; And
R
5And R
6C independently
5~C
15Alkyl or C
5~C
15Thiazolinyl.
14. such as project 13 described compound, wherein R
2aAnd R
2bDescribed nitrogen-protecting group be independently selected from Boc, Fmoc, TROC, TMS-ethyl carbonyl, cyanoethyl carbonyl, allyloxy carbonyl, (C
6H
5)
2C=, monoethyl diamide or trinitride.
15. such as project 13 described compounds, wherein n is 1; R
4C
7Alkyl; And R
5C
11Alkyl.
16. such as project 13 described compounds, wherein n is 1; R
1aIt is allyl group; R
2aHydrogen; R
2cBoc; R
4C
7Alkyl; And R
5C
11Alkyl.
17. such as project 16 described compounds, it has formula ER-819409:
18. such as project 13 described compounds, wherein n is 1; R
2aHydrogen; R
2c-C (O) CH
2C (O) R
6R
4C
7Alkyl; R
5C
11Alkyl; And R
6C
11Alkyl.
19. such as project 13 described compounds, wherein n is 0; R
1aIt is allyl group; R
2aHydrogen; R
2cBoc; R
4C
7Alkyl; And R
5C
11Alkyl.
20. such as project 19 described compounds, it has formula ER-821843:
21. such as project 13 described compounds, wherein n is 1; R
1aIt is allyl group; R
2aHydrogen; R
2cHydrogen; R
4C
7Alkyl; And R
5C
11Alkyl.
22. such as project 21 described compounds, it has formula ER-807284:
23. such as project 13 described compounds, wherein n is 0; R
1aIt is allyl group; R
2aHydrogen; R
2c-C (O) CH
2C (O) R
6R
4C
7Alkyl; R
5C
11Alkyl; And R
6C
11Alkyl.
24. such as project 23 described compounds, it has formula ER-807825:
25. the compound of formula (17):
Wherein:
R is hydrogen or C
1~C
6Alkyl;
R
2aAnd R
2bOne of be H, another is monovalence nitrogen-protecting group, perhaps R
2aAnd R
2bThe divalence nitrogen-protecting group together;
R
4C
5~C
12Alkyl or C
5~C
12Thiazolinyl; With
R
5C
5~C
15Alkyl or C
5~C
15Thiazolinyl.
26. such as project 25 described compound, wherein R
2aAnd R
2bNitrogen-protecting group be independently selected from Boc, Fmoc, TROC, TMS-ethyl carbonyl, cyanoethyl carbonyl, allyloxy carbonyl, (C
6H
5)
2C=, monoethyl diamide or trinitride.
27. such as project 25 described compounds, wherein R is hydrogen; R
2aAnd R
2bHydrogen; R
4C
7Alkyl; And R
5C
11Alkyl.
28. such as project 27 described compounds, it has formula ER-819120:
29. such as project 25 described compounds, wherein R is hydrogen; R
2aHydrogen; R
2bIt is nitrogen-protecting group; R
4C
7Alkyl; And R
5C
11Alkyl.
30. such as project 29 described compounds, it has formula ER-819302:
31. the compound of formula (18):
Wherein:
R
4C
5~C
12Alkyl or C
5~C
12Thiazolinyl; With
R
5C
5~C
15Alkyl or C
5~C
15Thiazolinyl.
32. such as project 31 described compounds, it has formula ER-819509:
33. crystal ER-806158, (R)-1-(((R)-4,5-dihydro-2-phenyl
Azoles-4-yl) methoxyl group) last of the ten Heavenly stems-3-alcohol, it has triclinic(crystalline)system and P1 spacer.
34. such as project 33 described crystal ER-806158, (R)--(((R)-4,5-dihydro-2-phenyl
Azoles-4-yl) methoxyl group) last of the ten Heavenly stems-3-alcohol, it is characterized in that lattice parameter is:
Description of drawings
Fig. 1 describes the structure of crystal ER-8016158.
Fig. 2 is the structure cell accumulation graph along a axle, and it is illustrated in the best figure of hydrogen bonded in the ER-806158 crystal, dotted line.
Fig. 3 describes powder x-ray diffraction (PXRD) figure of crystal ER-806158.
Fig. 4 represents the DSC thermogram of crystal ER-806158.
Fig. 5 represents the infrared spectra of crystal ER-806158.
Embodiment
Definition
Also as used herein according to the present invention, with following implication definition following term, unless expressly stated otherwise.
The below also will describe disclosed specific compound among the present invention and particular functional group's definition in more detail.For purposes of the invention, according to the periodic table of elements, CAS version, Handbook ofChemistry and Physics, 75
ThEd., inside front cover is determined chemical element, and usually limits as described therein specific functional group.In addition, at " Organic Chemistry ", Thomas Sorrell, University Science Books, among the Sausalito:1999, described vitochemical universal principle and particular functional part and reactive, its full content is incorporated this paper by reference into.In addition, it should be appreciated by those skilled in the art, synthetic method described herein is used the kinds of protect base.With regard to regard to this used term " protecting group ", refer to particular functional part for example O, S, P or N blocked temporarily so that reaction optionally the other reactive site in the polyfunctional compound carry out.In preferred embodiments, protecting group is with good selectivity of productive rate ground reaction, to obtain the substrate to the protection of designed stable reaction; Must by be easy to obtain, be preferably reagent nontoxic and that do not attack other functional group and come optionally deprotection base; Protecting group forms can segregative derivative (more preferably not producing new Stereocenter); And protecting group has minimum additional functionality, to avoid more reaction site.As describing in detail at this, can use oxygen, sulphur, nitrogen, phosphorus and carbon protecting group.
For example, in certain embodiments, as describing in detail at this, use some exemplary oxygen protecting group.These oxygen protecting groups include but not limited to methyl ether; the methyl ether that replaces (for example; MOM (methoxymethyl ether); MTM (methylthio group methyl ether); BOM (benzyloxy methyl ether); PMBM (to methoxyl group benzyloxy base methyl ether); etc.); the ether that replaces; the benzyl oxide that replaces; silicon ether (for example; TMS (trimethylsilyl ethers); TES (triethyl silicon ether); TIPS (triisopropyl silicon ether); TBDMS (tertiary butyl dimethyl-silicon ether); tribenzyl silicon ether; TBDPS (tert-butyl diphenyl silicon ether)); ester (for example; manthanoate; acetic ester; benzoic ether (Bz); trifluoro-acetate; the dichloro acetic acid ester, etc.); carbonic ether; cyclic acetal and ketal.The protecting group that is used for phosphorous acid ester oxygen and phosphoric acid ester oxygen comprises: for example, and such as the alkyl phosphate/phosphorous acid ester of methyl, ethyl, sec.-propyl, the tertiary butyl, cyclohexyl, 1-adamantyl and 2-trimethyl silyl third-2-thiazolinyl; Such as vinyl and allylic thiazolinyl phosphoric acid ester/phosphorous acid ester; Such as 2-cyanoethyl, 2-cyano group-1, ethyl phosphonic acid ester/phosphorous acid ester that the 2-of 1-dimethyl ethyl, 2-(trimethyl silyl) ethyl, 2-(4-nitrophenyl) ethyl, 2-(benzenesulfonyl) ethyl and 2-(benzene methylsulfonyl) ethyl replaces; Such as 2,2,2-, three chloroethyls, 2,2,2-three chloro-1,1-dimethyl ethyl, 2,2,2-three bromomethyl, 2, the haloethyl phosphoric acid ester/phosphorous acid ester of 3-dibromopropyl; Such as benzyl, 4-nitrobenzyl, 4-chlorobenzyl, 1-oxo bridge-4-methoxyl group-2-picolyl, fluorenyl-9-methyl, 5-benzisoxa
Azoles methylene, (C
6H
5)
2Benzyl phosphoric acid ester/phosphorous acid ester of C=; With the phenyl phosphate ester/phosphorous acid ester such as phenyl, 4-nitrophenyl and 4-chloro-phenyl-; And such as the silyl phosphoric acid ester/phosphorous acid ester of trimethyl silyl.
In other the exemplary embodiment, use nitrogen-protecting group at some.These nitrogen-protecting groups can be monovalence or divalence protecting group; ((for example comprise the urethanum of methyl, ethyl and replacement such as but not limited to carbamate; Troc), etc.), acid amides, cyclic imide derivative, N-alkyl and N-arylamines, imine derivative and enamine derivates etc.Amine protecting group is benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 9-fluorenyl methoxy carbonyl (Fmoc), 2 for example; 2,2-trichlorine ethoxy carbonyl (TROC), trimethyl silyl (TMS)-ethyl carbonyl, cyanoethyl carbonyl, allyloxy carbonyl or (C
6H
5)
2C=(phenylbenzene methylene radical) also can be mentioned.Some other exemplary protecting group describes in detail at this, yet, should be appreciated that the present invention is not limited to these protecting groups; On the contrary, utilize above-mentioned standard can determine at an easy rate also to use in the present invention multiple other protecting group of equal value.In addition, at " Protective Groups in Organic Synthesis " third edition Greene, T.W. and Wuts, P.G., Eds., John Wiley ﹠amp; Sons has described the kinds of protect base among the New York:1999, its full content is incorporated into by reference at this.
Should be appreciated that, compound described here can be replaced by the substituting group of any amount or functional moiety.Usually, term " replacement ", no matter whether its front adds term " randomly ", and is included in the substituting group in the formula of the present invention, refers to be replaced by specific substituting group to the hydrogen base in the fixed structure.When in any given structure can be selected from replacing more than substituting group of special groups more than a position time, can be identical or different at the substituting group of each position.As used in this, term " replacement " means to comprise the substituting group of all admissible organic compound.One widely aspect in, described admissible substituting group include organic compounds acyclic and ring-type, with side chain and not branched, carbocyclic ring and heterocycle, fragrance and non-aromatic, carbon and hetero atom substituents.For the present invention, heteroatoms for example nitrogen can have hydrogen substituting group and/or any admissible substituting group that satisfies the valent organic compound described herein of described heteroatoms.In addition, the present invention is also limited by the admissible substituting group of organic compound never in any form.The variation that substituent combination and the present invention predict is preferably those of stable compound that cause being formed for treating and prevent common aforesaid disease for example.Substituent example includes but not limited to the halogen substituting group, for example F, Cl, Br or I; Hydroxyl; C
1~C
6Alkoxyl group, for example-OCH
3,-OCH
2CH
3Or-OCH (CH
3)
2C
1~C
6Alkylhalide group, for example-CF
3,-CH
2CF
3Or-CHCl
2C
1~C
6Alkylthio; Amino; List and dialkyl amido;-NO
2-CN; Sulfate group etc.Common available substituent example in addition is by the particular explanation shown in the embodiment described here.
Preferably, referring at this used term " stable " that compound has is enough to allow the stability for preparing and the integrity that makes compound to keep the sufficiently long time to detect and preferably to keep the sufficiently long time to be used for the purpose at this detailed description.
As used in this, term " alkyl " comprises straight chain and branched alkyl.Similarly be given for other general term, such as " thiazolinyl ", " alkynyl " etc.In addition, as used in this, term " alkyl ", thiazolinyl ", " alkynyl " etc. comprise replacement and unsubstituted group.In certain embodiments, as used in this, " low alkyl group " is used for representing to have those alkyl (ring-type, acyclic, that replace, unsubstituted, branched or not branched) of 1~6 carbon atom.In other embodiments, preferred C
1-4, C
2-4, C
1-3Or C
3-6Alkyl or alkenyl.
In certain embodiments, used alkyl, thiazolinyl and alkynyl comprises for 1~20 aliphatic carbon atom of alkyl and is used for 2~20 carbon atoms of thiazolinyl and alkynyl in the present invention.In some other embodiment, used alkyl, thiazolinyl and alkynyl comprise 1~15 aliphatic carbon atom in the present invention.In other embodiments, used alkyl, thiazolinyl and alkynyl comprises 1~8 aliphatic carbon atom in the present invention.In other embodiment, used alkyl, thiazolinyl and alkynyl comprise 1~6 aliphatic carbon atom in the present invention.In other embodiments, used alkyl, thiazolinyl and alkynyl comprises 1~4 carbon atom in the present invention.Therefore exemplary aliphatic group includes but not limited to such as methyl, ethyl, n-propyl, sec.-propyl, allyl group, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, sec.-amyl sec-pentyl secondary amyl, isopentyl, tert-pentyl, n-hexyl, Sec-Hexyl part etc., and they again can be with one or more substituting groups.Thiazolinyl includes but not limited to such as vinyl, propenyl, butenyl, 1-methyl-2-butene-1-base etc.Representational alkynyl includes but not limited to ethynyl, 2-propynyl (propargyl), 1-proyl etc.
As used in this, term " alicyclic ring " refers to the compound of the characteristic of combining fat family and ring compound, includes but not limited to aliphatic hydrocarbon and bridge ring alkyl compounds ring-type or many rings, and it is randomly replaced by one or more functional groups.As skilled in the art to understand, " alicyclic ring " is intended to include but not limited to cycloalkyl, cycloalkenyl group and cycloalkynyl radical part at this, and it is randomly replaced by one or more functional groups.Therefore, exemplary alicyclic group for example include but not limited to cyclopropyl ,-CH
2-cyclopropyl, cyclobutyl ,-CH
2-cyclobutyl, cyclopentyl ,-CH
2-cyclopentyl-n, cyclohexyl ,-CH
2-cyclohexyl, cyclohexenyl ethyl, cyclohexyl ethyl, norcamphyl part etc., they again can be with one or more substituting groups.
Refer to be connected to the parent molecule part such as the previous alkyl or cycloalkyl that limits by Sauerstoffatom or by sulphur atom at this used term " alkoxyl group " (or " alkyl oxy ") or " alkylthio ".In certain embodiments, alkyl or cycloalkyl comprises 1~20 aliphatics or alicyclic carbon atom.In some other embodiment, alkyl or cycloalkyl comprises 1~10 aliphatics or alicyclic carbon atom.In other embodiments, used alkyl, thiazolinyl and alkynyl comprises 1~8 aliphatics or alicyclic carbon atom in the present invention.In other embodiment, alkyl comprises 1~6 aliphatics or alicyclic carbon atom.In other embodiments, alkyl comprises 1~4 aliphatics or alicyclic carbon atom.The example of alkoxyl group includes but not limited to methoxyl group, oxyethyl group, propoxy-, isopropoxy, n-butoxy, tert.-butoxy, neopentyl oxygen and positive hexyloxy.The example of alkylthio includes but not limited to methylthio group, ethylmercapto group, rosickyite base, isopropyl sulfenyl, positive butylthio etc.
Term " alkylamino " refers to have-group of NHR ' structure, and wherein R ' is the alkyl or cycloalkyl that limits at this.Term " dialkylamino " refers to have-N (R ')
2The group of structure, each R ' that wherein exists is the alkyl or cycloalkyl that limits at this independently.Term " aminoalkyl group " refers to have NH
2The group of R '-structure, wherein R ' is the alkyl or cycloalkyl that limits at this.In certain embodiments, alkyl comprises 1~20 aliphatics or alicyclic carbon atom.In some other embodiment, alkyl or cycloalkyl comprises 1~10 aliphatics or alicyclic carbon atom.In other embodiments, used alkyl, thiazolinyl and alkynyl comprises 1~8 aliphatics or alicyclic carbon atom in the present invention.In other embodiment, alkyl or cycloalkyl comprises 1~6 aliphatics or alicyclic carbon atom.In other embodiments, alkyl or cycloalkyl comprises 1~4 aliphatics or alicyclic carbon atom.The example of alkylamino includes but not limited to methylamino-, ethylamino, isopropylamino etc.
Usually, refer to the stable list that preferably has 3~14 carbon atoms or many rings, heterocycle at this used term " aryl " and " heteroaryl ", encircle and the unsaturated part of many heterocycles more, its each can be substituted or not be substituted.Should also be appreciated that, aryl is connected with heteroaryl moieties and is connected by alkyl or assorted moieties as defined in this, and therefore also comprise-(alkyl) aryl ,-(assorted alkyl) aryl ,-(assorted alkyl) aryl and-(assorted alkyl) heteroaryl moieties.Therefore, as used in this, term " aryl or heteroaryl " and " aryl, heteroaryl ,-(alkyl) aryl ,-(assorted alkyl) aryl ,-(assorted alkyl) aryl and-(assorted alkyl) heteroaryl " be interchangeable.Substituting group includes but not limited to arbitrarily previously mentioned substituting group, namely replaces the substituting group of fats portion or other parts disclosed herein, consequently forms stable compound.In certain embodiments of the invention, " aryl " refers to have list or the bicyclic carbocyclic system of one or two aromatic ring, includes but not limited to phenyl, naphthyl, tetralyl, indanyl, indenyl etc.In certain embodiments of the invention, refer to have the ring-type aryl of five to ten annular atomses at this used term " heteroaryl ", one of them annular atoms is selected from S, O and N; Zero, one or two annular atomses are other heteroatomss that are independently selected from S, O and N; And remaining annular atoms is carbon, and described group is connected to the rest part of molecule by annular atoms arbitrarily, for example pyridyl, pyrazinyl, pyrimidyl, pyrryl, pyrazolyl, imidazolyl, thiazolyl,
Azoles base, different
Azoles base, thiadiazolyl group,
Di azoly, thienyl, furyl, quinolyl, isoquinolyl etc.
Should be appreciated that, aryl and heteroaryl (comprising aryl bicyclic) can be unsubstituted or replace, and wherein replaces to comprise independently with one or more common aforesaid substituting groups arbitrarily and substitute one or more hydrogen atoms on it.Usually available substituent other example is by the particular explanation shown in the embodiment described herein.
Specifically refer to have 3~7 at this used term " cycloalkyl ", the group of preferred 3~10 carbon atoms.Suitable cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl etc., and it is the same with other alicyclic ring, heterolipid ring or heterocyclic moiety, is optionally replaced by one or more common aforesaid substituting groups.Similarly rule is applicable to other general term, such as " cycloalkenyl group ", " cycloalkynyl radical " etc.In addition, should be appreciated that as above and can comprise aryl or the heteroaryl moieties that is fused on it with any aliphatics described herein or assorted aliphatic portion.Usually available substituent other example is by the particular explanation shown in the embodiment described herein.
Refer to the aliphatic portion that the one or more carbon atoms in the main chain have been replaced by heteroatoms at this used term " assorted aliphatic ".Therefore, assorted aliphatic group refers to contain the aliphatic chain that for example substitutes one or more oxygen, sulphur, nitrogen, phosphorus or the Siliciumatom of carbon atom.Assorted aliphatic portion can be branched or linear not branched.In certain embodiments, assorted aliphatic portion replaces by the one or more hydrogen atoms that substitute on it independently with one or more common aforesaid substituting groups.Usually available substituent other example is by the particular explanation shown in the embodiment described herein.
Refer to the compound in conjunction with the characteristic of assorted aliphatics and ring compound at this used term " assorted alicyclic ", include but not limited to saturated and undersaturated single or encircle heterocycle more, such as morpholinyl, pyrrolidyl, furyl, thienyl, pyrryl etc., it is randomly by as defined in this one or more functional groups replacement.
In addition, should be appreciated that, as above can comprise aryl or the heteroaryl moieties that is fused on it with any alicyclic or assorted alicyclic part described herein.Usually available substituent other example is by the particular explanation shown in the embodiment described herein.
Refer to be selected from the atom of fluorine, chlorine, bromine and iodine at this used term " halogen " and " halogen ".
The alkyl that term " alkylhalide group " represents to have as defined above one, two or three halogen atoms are connected thereto, and take groups such as chloromethyl, bromotrifluoromethane, trifluoromethyl as example.
Refer to non-aromatic 5-at this used term " Heterocyclylalkyl " or " heterocycle ", 6-or 7-unit ring or many cyclic groups, include but not limited to comprise and have the oxygen of being independently selected from, two or three cyclic groups to three heteroatomic six-rings that condense of sulphur and nitrogen, wherein (i) each 5-unit ring has 0~1 two key and each 6-unit ring has 0~2 two key, (ii) nitrogen and sulfur heteroatom can be randomly oxidized, (iii) nitrogen heteroatom can be randomly quaternized, and (iv) arbitrarily above-mentioned heterocycle can be fused on aromatic ring replacement or unsubstituted or the hetero-aromatic ring.Typical heterocycle include but not limited to pyrrolidyl, pyrazolinyl, pyrazolidyl, imidazolinyl, imidazolidyl, piperidyl, piperazinyl,
Oxazolidinyl, different
Oxazolidinyl, morpholinyl, thiazolidyl, isothiazole alkyl and tetrahydrofuran base.In certain embodiments, use " Heterocyclylalkyl of replacement or heterocycle " group, and refer to as used in this as defined above by substituting independently Heterocyclylalkyl or the heterocyclic group that the one or more hydrogen atoms on it replace with one or more common aforesaid substituting groups.Usually available substituent other example is by the particular explanation shown in the embodiment described herein.
That comprise replacement at this used term " aliphatic ", " assorted aliphatic ", " alkyl ", " thiazolinyl ", " alkynyl ", " assorted alkyl ", " assorted thiazolinyl ", " assorted alkynyl " etc. and unsubstituted, saturated and undersaturated and linear and branched group.Similarly, term " alicyclic ", " assorted alicyclic ", " Heterocyclylalkyl ", " heterocycle " etc. that comprise replacement with unsubstituted and saturated and undersaturated group.In addition, term " cycloalkyl ", " cycloalkenyl group ", " cycloalkynyl radical ", " Heterocyclylalkyl ", " heterocycloalkenyl ", " heterocycle alkynyl ", " aryl ", " heteroaryl " etc. comprise replacement and unsubstituted group.
Therefore in addition, E6020 comprises asymmetric carbon atom, and can be used as steric isomer and exist, i.e. enantiomorph and diastereomer.Those skilled in the art will recognize that method of the present invention can be suitable for preparing the arbitrarily all possible steric isomer of E6020.Although the preparation of specific isomer is provided at this embodiment that provides, has thought that the method for the preparation of other steric isomer of E6020 falls within the scope of the invention.
Detailed Description Of The Invention
On the one hand, the invention provides the method for a kind of TLR-4 receptor stimulant E6020 for the synthesis of having following structure:
E6020 is effective TLR-4 receptor stimulant, and therefore described compound is used as immunological adjuvant when for example using altogether for the vaccine of bacteriosis and virus disease with antigen.For example, E6020 can be used in combination with any suitable antigen or vaccine component that for example is selected from from the antigen-agent of the antigen of cause of disease and non-pathogenic organism, virus and fungi.As another example, E6020 can with have protein, peptide, antigen and the vaccine of pharmacologically active to be used in combination to for example smallpox, yellow jack, cancer, pest heat, cholera, fowl pox, scarlet fever, diphtheria, tetanus, Whooping cough, influenza, rabies, parotitis, measles, foot and mouth disease and poliomyelitic symptom and the state of an illness.In certain embodiments, E6020 and antigen exist with significant quantity separately, to cause immunne response when it is applied to vaccinated host animal, tire or ovum.
On the other hand, the present invention includes method for the synthesis of any steric isomer of TLR-4 receptor stimulant E6020.Therefore, be provided for preparing the method for the compound with following structure at this:
I. the dimeric preparation of phosphoric acid ester urea groups
In certain embodiments, the inventive method comprises the steps:
(a) make the compound with following structure:
Wherein, R
1aAlkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, assorted alkyl, assorted thiazolinyl, assorted alkynyl, Heterocyclylalkyl, heterocycloalkenyl, heterocycle alkynyl, aryl, heteroaryl, phosphorous acid ester oxygen protecting group or phosphoric acid ester oxygen protecting group; With
R
2aAnd R
2bHydrogen or suitable nitrogen-protecting group, perhaps R independently of one another
2aAnd R
2bForm together 5-or 6-unit heterocycle; R wherein
2aAnd R
2bBe not hydrogen simultaneously;
React under suitable condition with phosgene, form the urea groups dimer with following structure:
(b) make under suitable condition urea groups dimer (2) deprotection that in step (a), forms, have the dimer (3) of the part deprotection of following structure with formation:
(c) make under suitable condition the dimer of the part deprotection that in step (b), forms and suitable reagent react, have the dimer (4) of the protection of following structure with formation:
With
(d) dimer of using under suitable condition one or more suitable agent treated in step (c), to form, the sodium salt that has following structure with formation:
In certain embodiments, above-claimed cpd 1~5 has following stereochemistry:
In other embodiments, the dimeric step of using under suitable condition one or more suitable agent treated to form in step (c) causes having the formation of the compound of following structure:
Then it is purified, and produces corresponding disodium salt:
In certain embodiments, as implied above those for example, each R of appearance
1aHydrogen, C independently
1~C
6Alkyl, C
3~C
6Thiazolinyl, C
3~C
6Alkynyl or phosphorous acid ester oxygen protecting group or phosphoric acid ester oxygen protecting group.In some exemplary embodiment, each R
1aIt is allyl group.
In certain embodiments, R
2aAnd R
2bBe independently of one another hydrogen, alkyl, thiazolinyl ,-C (=O) R
x,-C (=O) OR
x,-SR
x, SO
2R
x, perhaps R
2aAnd R
2bForm together and have=CR
xR
yThe part of structure, wherein R
2aAnd R
2bBe not hydrogen and R simultaneously
xAnd R
yBe independently of one another hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, assorted alkyl, assorted thiazolinyl, assorted alkynyl, Heterocyclylalkyl, heterocycloalkenyl, heterocycle alkynyl, assorted aliphatics, assorted alicyclic, aryl, heteroaryl ,-C (=O) R
AOr-ZR
A, wherein Z be-O-,-S-,-NR
B, each R that wherein occurs
AAnd R
BHydrogen or alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, assorted alkyl, assorted thiazolinyl, assorted alkynyl, Heterocyclylalkyl, heterocycloalkenyl, heterocycle alkynyl, assorted aliphatics, assorted alicyclic, aryl or heteroaryl moieties independently.In some exemplary embodiment, R
2aHydrogen and R
2b-C (=O) OR
x, R wherein
xThat replace or unsubstituted low alkyl group.At some in other exemplary embodiment, R
2aHydrogen and R
2b-C (=O) OtBu.
In certain embodiments, the reaction conditions in the step (a) is included in the phosgene in the appropriate solvent.In some exemplary embodiment, described solvent is CH
2Cl
2, toluene or its combination.In certain embodiments, the reaction conditions in the step (a) also comprises weak base.In some exemplary embodiment, described weak base is NaHCO
3The aqueous solution.
In certain embodiments, the deprotection reaction condition in the step (b) is included in the strong acid in the appropriate solvent.In some exemplary embodiment, described solvent is CH
2Cl
2At some in other exemplary embodiment, R
2aHydrogen, R
2bBe-C (=O) OtBu, and described strong acid is TFA.
In certain embodiments, the reagent in the step (c) is 3-oxo-tetradecanoic acid derivative.As used in this, " carboxylic acid derivative " (for example, 3-oxo-tetradecanoic acid or dodecylic acid derivative) refer to the RC (=O) compound of X structure, wherein R is carboxyl, and X is suitable for by forming the chemical group of acid amides with primary amine reaction, and perhaps X is can be by chemical conversion with by forming the chemical group of acid amides with primary amine reaction.In certain embodiments, X be halogen, hydroxyl ,-OR ,-SH ,-SR or-C (halogen)
3Wherein, R is alkyl or aryl.In some exemplary embodiment, reagent is 3-oxo-tetradecanoic acid.In certain embodiments, the reagent in the step (c) is 3-oxo-tetradecanoic acid and is used for making the dimer of deprotection and the reaction conditions of reagent react comprise alkali.In certain embodiments, described alkali is I-hydroxybenzotriazole.In certain embodiments, alkali is Hunig ' s alkali.In certain embodiments, the reaction conditions of step (c) comprises the carboxylic acid activating agent, for example DCC.In certain embodiments, described carboxylic acid activating agent is 1-[3-(dimethylamino) propyl group]-the 3-ethyl carbodiimide.In certain embodiments, described carboxylic acid activating agent is HBTU.
In some other embodiment, each R of appearance
1aBe allyl group, and the reaction conditions in the step (d) is included in the Pd (PPh in the appropriate solvent
3)
4In some exemplary embodiment, the treatment condition in the step (d) also comprise triphenyl phosphine and phenyl silane.In some exemplary embodiment, solvent is THF.
In other embodiments, purifying has the compound of following structure:
Comprise chromatographic separation and use alkaline purification.In some exemplary embodiment, described purge process comprises (i) ion-exchange chromatography, (ii) C-4Kromasil wash-out and (iii) usefulness NaOAc aqueous solution processing.In some exemplary embodiment, described purge process comprises (i) Biotage KP-silicon-dioxide chromatogram, (ii) Biotage KP HS-C18 chromatogram and (iii) usefulness NaOAc aqueous solution processing.
II. for the preparation of the method for intermediate 1
In some exemplary embodiment, the compound with following structure is prepared by a method comprising the following steps:
Wherein, R
1aHydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, assorted alkyl, assorted thiazolinyl, assorted alkynyl, Heterocyclylalkyl, heterocycloalkenyl, heterocycle alkynyl, aryl, heteroaryl or phosphorous acid ester oxygen protecting group or phosphoric acid ester oxygen protecting group; With
R
2aAnd R
2bHydrogen or suitable nitrogen-protecting group, perhaps R independently of one another
2aAnd R
2bForm together 5-or 6-unit heterocycle; R wherein
2aAnd R
2bBe not hydrogen simultaneously;
(a) make the alcohol with following structure:
Glycol reaction with the suitable part protection with following structure:
Wherein ,-OX
1Represent suitable leaving group;
The alcohol that has following structure with formation:
(b) make under suitable condition alcohol 8 and suitable dodecylic acid derivatives reaction, the ester that has following structure with formation:
(c) make under suitable condition ester 9 deprotections, the azanol that has following structure with formation:
(d) partly protect under suitable condition azanol 10, the alcohol that has following structure with formation:
Wherein, R
2aAnd R
2bAs above limit;
(e) use under suitable condition one or more suitable agent treated alcohol 11, to form tool
The phosphoric acid ester that following structure is arranged:
Wherein, R
1aHydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, assorted alkyl, assorted thiazolinyl, assorted alkynyl, Heterocyclylalkyl, heterocycloalkenyl, heterocycle alkynyl, aryl or heteroaryl, phosphorous acid ester oxygen protecting group or phosphoric acid ester oxygen protecting group; With
R
3aAnd R
3bHydrogen or suitable nitrogen-protecting group, perhaps R independently of one another
3aAnd R
3bForm together 5-or 6-unit heterocycle; R wherein
3aAnd R
3bBe not hydrogen simultaneously; With
(f) make under suitable condition 12 deprotections partly, form amine 1:
In certain embodiments, each R of appearance
1aOn the spot be hydrogen, C
1~C
6Alkyl, C
3~C
6Thiazolinyl, C
3~C
6Alkynyl or phosphorous acid ester oxygen protecting group or phosphoric acid ester oxygen protecting group.In some exemplary embodiment, each R of appearance
1aIt is allyl group.
In certain embodiments, R
2aAnd R
2bBe independently of one another hydrogen, alkyl, thiazolinyl ,-C (=O) R
x,-C (=O) OR
x,-SR
x, SO
2R
x, perhaps R
2aAnd R
2bForm together and have=CR
xR
yThe part of structure, wherein R
2aAnd R
2bBe not hydrogen and R simultaneously
xAnd R
yBe independently of one another hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, assorted alkyl, assorted thiazolinyl, assorted alkynyl, Heterocyclylalkyl, heterocycloalkenyl, heterocycle alkynyl, assorted aliphatics, assorted alicyclic, aryl, heteroaryl ,-C (=O) R
AOr-ZR
A, wherein Z be-O-,-S-,-NR
B, each R that wherein occurs
AAnd R
BHydrogen or alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, assorted alkyl, assorted thiazolinyl, assorted alkynyl, Heterocyclylalkyl, heterocycloalkenyl, heterocycle alkynyl, assorted aliphatics, assorted alicyclic, aryl or heteroaryl moieties independently.In some exemplary embodiment, R
2aHydrogen and R
2b-C (=O) OR
x, R wherein
xThat replace or unsubstituted low alkyl group.At some in other exemplary embodiment, R
2aHydrogen and R
2b-C (=O) OtBu.
In some exemplary embodiment, X
1It is tosyl group.
In certain embodiments, the dodecylic acid derivative of step (b) is dodecylic acid.In certain embodiments, the reagent of step (b) is dodecylic acid and is used for making the reaction conditions of alcohol 8 reactions to comprise alkali.In certain embodiments, described alkali is DMAP (DMAP).In certain embodiments, the reaction conditions of step (b) comprises the carboxylic acid activating agent, for example DCC.In certain embodiments, described carboxylic acid activating agent is 1-[3-(dimethylamino) propyl group]-the 3-ethyl carbodiimide.
In certain embodiments, the deprotection reaction condition of step (c) comprises catalytic hydrogenolysis and suitable solvent.In some exemplary embodiment, the deprotection reaction condition of step (c) comprises H
2And Pd/C.In some exemplary embodiment, solvent is Virahol (IPA).
In some exemplary embodiment, R
2aHydrogen and R
2b-C that (=O) OtBu, the reaction conditions of step (d) comprises tert-Butyl dicarbonate and suitable solvent.In certain embodiments, described solvent is alcohol.In some exemplary embodiment, solvent is Virahol (IPA).
In certain embodiments, step (e) comprising:
(i) original position forms the amino phosphorous acid ester (phosphoramidous acid ester) with following structure:
R wherein
4aAnd R
4bLow alkyl group independently; With
(ii) original position forms the phosphorous acid ester with following structure:
Wherein, R
1a, R
2a, R
2b, R
3aAnd R
3bAs above limit.
In some other embodiment, treatment step (e) comprises phosphorylating agent, and causes the original position of amino phosphorous acid ester 13 to form.In some exemplary embodiment, described phosphorylating agent is the allyl group tetraisopropylphosph-ro phosphoryl diamine (tetraisopropylphosphorodiamidite) in the presence of dialkylamine.In some other embodiment, treatment step (e) comprises the trifluoroacetic acid pyridine
In some exemplary embodiment, dialkylamine is that Diisopropylamine and described amino phosphorous acid ester 13 have following structure:
In certain embodiments, treatment step (e) comprises that original position forms amino phosphorous acid ester 13, and the thanomin with the protection with following structure reacts subsequently:
Wherein, R
3aAnd R
3bHydrogen or suitable nitrogen-protecting group, perhaps R independently of one another
3aAnd R
3bForm together 5-or 6-unit heterocycle; R wherein
3aAnd R
3bBe not hydrogen simultaneously.In some exemplary embodiment, R
3aAnd R
3bBe independently of one another hydrogen, alkyl, thiazolinyl ,-C (=O) R
x,-C (=O) OR
x,-SR
x, SO
2R
x, perhaps R
3aAnd R
3bForm together and have=CR
xR
yThe part of structure, wherein R
3aAnd R
3bBe not hydrogen and R simultaneously
xAnd R
yBe independently of one another hydrogen, alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, assorted alkyl, assorted thiazolinyl, assorted alkynyl, Heterocyclylalkyl, heterocycloalkenyl, heterocycle alkynyl, assorted aliphatics, assorted alicyclic, aryl, heteroaryl ,-C (=O) R
AOr-ZR
A, wherein Z be-O-,-S-,-NR
B, each R that wherein occurs
AAnd R
BHydrogen or alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, assorted alkyl, assorted thiazolinyl, assorted alkynyl, Heterocyclylalkyl, heterocycloalkenyl, heterocycle alkynyl, assorted aliphatics, assorted alicyclic, aryl or heteroaryl moieties independently.In some exemplary embodiment, R
3aHydrogen and R
3b-C (=O) OR
x, R wherein
xIt is aralkyl.At some in other exemplary embodiment, R
3aHydrogen and R
3b-C (=O) OR
x, R wherein
x9-fluorene methyl (that is, R
3bFmoc).
In some exemplary embodiment, treatment step (e) comprises the reaction in-situ of the thanomin 15 of amino phosphorous acid ester 13 and protection, wherein R
3aHydrogen and R
3bBe Fmoc, and reaction conditions comprise acetic acid and trifluoroacetic acid pyridine
In certain embodiments, treatment step (e) comprises that the original position of phosphorous acid ester 14 forms, and oxidation forms phosphoric acid ester 12 in the presence of suitable oxygenant subsequently:
In some exemplary embodiment, described oxygenant is H
2O
2
In certain embodiments, R
2aHydrogen and R
2b-C that (=O) OtBu, the reaction conditions of step (f) comprises dialkylamine and suitable solvent.In some exemplary embodiment, dialkylamine is dimethylamine.In some exemplary embodiment, solvent is THF.
In certain embodiments, intermediate 6-13,13a and 14 have following stereochemistry:
Synthesis summary
Those skilled in the art can utilize the document of the phospholipids chemistry that has existed, and combine with the information that this paper comprises, to instruct synthesis strategy, protecting group and other materials and methods for the synthesis of E6020 and steric isomer thereof.
Various patent documentations and providing useful background information in preparation aspect the specific monose initial feed at this other reference of quoting.Particularly, 6,551, described specific reagent and initial feed in 600,6,290,973 and 6,521,776, its full content is incorporated into by reference at this.
In addition, those skilled in the art can pay close attention to that the document provides about concrete guide and embodiment for the synthesis of the exemplary intermediate of E6020 and steric isomer thereof.
Above-claimed cpd in E6020 is synthetic has heptyl and undecyl side chain.In the E6020 analogue with different alkyl chain length synthetic, by using suitable reagent, these side chains can have different length.Therefore, the present invention relates to the to have following formula compound of (15):
In formula (15), A is-(CH
2)
x-O-or covalent linkage, n be 0 or 1, x be 1~6.When A is-(CH
2)
xDuring-O-, methylene radical is connected to NR
3aR
3bNitrogen-atoms on, and oxygen is connected on the phosphorus atom of phosphorous acid ester or bound phosphate groups.Preferably, x is 2~4, and most preferably is 2.When n was 0, the compound of formula (15) contained the phosphorous acid ester group.When n was 1, the compound of formula (15) contained bound phosphate groups.
R
1aHydrogen, C
1~C
6Alkyl, C
3~C
6Thiazolinyl, C
3~C
6Alkynyl or phosphorous acid ester oxygen protecting group or phosphoric acid ester oxygen protecting group.Described protecting group is known in this area, and what it was exemplary enumerates as mentioned above.Particularly preferred radicals R
1aIt is allyl group.
In formula (15), R
2aAnd R
2bOne of be H, another is the monovalence nitrogen-protecting group; Perhaps R
2aAnd R
2bThe divalence nitrogen-protecting group together.For R
3aAnd R
3b, when A is-(CH
2During)-O-, R
3aAnd R
3bOne of be H, another is the monovalence nitrogen-protecting group; Perhaps R
3aAnd R
3bThe divalence nitrogen-protecting group together.When A is covalent linkage, R
3aAnd R
3bBe independently selected from C
1~C
6Alkyl or be together-(CH
2)
4-,-(CH
2)
5-or-(CH
2)
2O (CH
2)
2-.Preferably, when A is covalent linkage, R
3aAnd R
3bC
2~C
6Alkyl, for example ethyl, propyl group or butyl and sec.-propyl more preferably.
In the compound of formula (15), with R
2aAnd R
2bProtecting group on the nitrogen that connects can remove under the first condition that is selected from acidity, alkalescence, oxidation and reductive condition; With R
3aAnd R
3bProtecting group on the nitrogen that connects can remove under the second condition that is selected from its excess-three kind condition that is different from described first condition.Preferred nitrogen-protecting group is selected from Boc, Fmoc, TROC, TMS-ethyl carbonyl, cyanoethyl carbonyl, allyloxy carbonyl, (C
6H
5)
2C=, monoethyl diamide or trinitride.Generally speaking, there is the condition of Four types to can be used for removing nitrogen-protecting group, i.e. acidity, alkalescence, oxidation or reductive condition.In preferred embodiments, under one of these four kinds of conditions, optionally remove a nitrogen-protecting group, and use one of three kinds of remaining conditions optionally to remove another nitrogen-protecting group.In one embodiment, remove nitrogen-protecting group with gentle acid or gentle alkaline condition respectively.
With R
2aAnd R
2bThe nitrogen that connects can be used Boc radical protection and and R
3aAnd R
3bThe nitrogen that connects can be used the Fmoc radical protection, and perhaps vice versa.The Boc group optionally under acidic conditions (the at room temperature methylsulfonic acid in the solvent of for example methylene dichloride, trifluoroacetic acid or formic acid) remove.The Fmoc group can for example at room temperature optionally remove when the secondary amine among the THF such as piperidines or dimethylamine when using at solvent.
Scheme as an alternative is with R
2aAnd R
2bThe nitrogen that connects can be used Troc radical protection and and R
3aAnd R
3bThe nitrogen that connects can be used the Fmoc radical protection, and perhaps vice versa.The Fmoc group can optionally remove under aforesaid condition, and the Troc group can be in the lower fracture of reductive condition (for example zinc in THF, water).
In another example, with R
2aAnd R
2bThe nitrogen that connects can be used Troc radical protection and and R
3aAnd R
3bThe nitrogen that connects can be used the Boc radical protection, and perhaps vice versa.The Troc group can be in the lower fracture of reductive condition (for example zinc in THF, water), and the Boc group can optionally remove under aforesaid condition.
R
4C
5~C
12Alkyl or C
5~C
12Thiazolinyl.R
4C
5~C
12Alkyl, be preferably C
5~C
9Alkyl, C more preferably
7Alkyl, and most preferably be n-heptyl.
R
5C
5~C
15Alkyl or C
5~C
15Thiazolinyl.R
5C
5~C
15Alkyl, be preferably C
7~C
13Alkyl, C more preferably
11Alkyl, and most preferably be the n-undecane base.
The salt of the compound of formula (15) can occur in building-up process, and compound that perhaps also can be by making formula (I) and acid or alkali reaction obtain.Be preferably acid salt.
The compound of preferred formula (15) is as follows: (a) wherein, A is-(CH
2)
2-O-, n are 0, R
4C
7Alkyl, and R
5C
11Alkyl; (b) wherein, A is-(CH
2)
2-O-, n are 1, R
4C
7Alkyl, and R
5C
11Alkyl; (c) wherein, A is covalent linkage, and n is 0, R
4C
7Alkyl, and R
5C
11Alkyl; (d) wherein, A is covalent linkage, and n is 0, R
3aAnd R
3bThe sec.-propyl of respectively doing for oneself, R
4C
7Alkyl, and R
5C
11Alkyl.
Such intermediate is for the preparation of E6020 analogue and precursor with following formula (16):
In formula (16), (I) is described such as following formula, and n is 0 or 1.R
1aHydrogen, C
1~C
6Alkyl, C
2~C
6Thiazolinyl, C
2~C
6Alkynyl, phosphorous acid ester oxygen protecting group or phosphoric acid ester oxygen protecting group.The preferred radicals R that is used for
1aSubstituting group with discussed above those are identical.For example, R
2aAnd R
2cOne of be H, another be the monovalence nitrogen-protecting group or-C (O) CH
2C (O) R
6Perhaps R
2aAnd R
2cThe divalence nitrogen-protecting group together.Except R
2aOr R
2cOne of also can be preferably-C (O) CH
2C (O) R
6Outside, preferably be used for R
2aAnd R
2cGroup and discussed above for R
2aAnd R
2bThose are identical.R
4C
5~C
12Alkyl or C
5~C
12Thiazolinyl, have the preferred group identical with formula (15).R
5And R
6C independently
5~C
15Alkyl or C
5~C
15Thiazolinyl, have with above-mentioned for R
5Those identical preferred substituents.
The compound of preferred formula (16) is as follows: (a) wherein, n is 1, R
4C
7Alkyl, and R
5C
11Alkyl; (b) wherein, n is 1, R
1aAllyl group, R
2aHydrogen, R
2cBoc, R
4C
7Alkyl, and R
7C
11Alkyl; (c) wherein, n is 1, R
2aHydrogen, R
2c-C (O) CH
2C (O) R
6, R
4C
7Alkyl, R
5C
11Alkyl, and R
6C
11Alkyl; (d) wherein, n is 0, R
1aAllyl group, R
2aHydrogen, R
2cBoc, R
4C
7Alkyl, and R
5C
11Alkyl; (e) wherein, n is 1, R
1aAllyl group, R
2aHydrogen, R
2cHydrogen, R
4C
7Alkyl, and R
5C
11Alkyl; (f) wherein, n is 0, R
1aAllyl group, R
2aHydrogen, R
2c-C (O) CH
2C (O) R
6, R
4C
7Alkyl, R
5C
11Alkyl, and R
6C
11Alkyl.
The salt of the compound of formula (16) can occur in synthetic process, and compound that perhaps also can be by making formula (I) and acid or alkali reaction obtain.Be preferably acid salt.
The present invention also comprises the compound of formula (17):
In formula (17), R is hydrogen or C
1~C
6Alkyl and be preferably hydrogen.R in the formula (17)
2aAnd R
2bOne of be H, another is the monovalence nitrogen-protecting group; Perhaps R
2aAnd R
2bThe divalence nitrogen-protecting group together.R
2aAnd R
2bPreferred group be for those of above-mentioned formula (15).R
4C
5~C
12Alkyl or C
5~C
12Thiazolinyl and R
5C
5~C
15Alkyl or C
5~C
15Thiazolinyl.R
4And R
5Preferred group also be for those of above-mentioned formula (15).
The compound of preferred formula (17) comprises following these compounds: (a) wherein, R is hydrogen, R
2aAnd R
2bHydrogen, R
4C
7Alkyl, and R
5C
11Alkyl; (b) wherein, R is hydrogen, R
2aHydrogen, R
2bNitrogen-protecting group, R
4C
7Alkyl, and R
5C
11Alkyl.
The present invention also comprises the compound of formula (18):
In formula (18), R
4C
5~C
12Alkyl or C
5~C
12Thiazolinyl; And R
5C
5~C
15Alkyl or C
5~C
15Thiazolinyl.R
6And R
7Preferred group as mentioned above.The compound of preferred formula (18) is ER-819509.
As follows for the example of implementing synthetic method of the present invention, in the specific examples of synthetic route 1~5 and this paper, describe in detail.Should be appreciated that, method described herein is applicable to each and equivalent thereof in the compound disclosed herein.In addition, reagent and initial feed are known to those skilled in the art.Although following synthetic route is described intermediate and the protecting group of particular exemplary, should be appreciated that and use alternative initial feed, protecting group and/or reagent can produce other intermediate, this is considered within the scope of the invention.
In some exemplary embodiment of the present invention, the preparation of ester ER-819059 realizes by three steps, and the functionalized glycol ER-028694 in group selectivity ground with suitable is converted into leaving group with primary hydroxyl thus.For example, the primary hydroxyl of glycol ER-028694 by tosylation to obtain corresponding adducts ER-028695.Then tolylsulfonyl ester ER-028695 and pure ER-807277 coupling in the presence of alkali (for example NaHMDS) is to obtain corresponding ether ER-806158.With lauric acid esterification alcohol ER-806158, subsequently hydrogenolysis phenyl dihydro
The azoles group obtains azanol ER-819120.Amino Boc protection obtains ER-819302.
Synthetic route 2
Synthetic route 3
Described in synthetic route 2 and 3, can the ER-819302 that Boc-protects be converted into E6020 with 6 steps.For example, phosphorylation ER-819302 in the presence of two (allyloxy) diisopropylaminoethyl phosphine and Diisopropylamine is subsequently with FmocNH (CH
2)
2OH reaction in-situ and oxidation (for example, hydrogen peroxide), to form the intermediate E R-819344 of phosphorylation, it is (for example, Me under suitable condition
2NH) form the intermediate E R-819385 of deprotection during deprotection.ER-819385 and phosgene are under proper condition (for example, at NaHCO
320% phosgene under the aqueous solution exists in toluene) reaction causes the formation of bisphosphate ER-819409.Use suitable acid for example TFA make the secondary amine deprotection of the Boc-protection on ER-819409, obtain diamines intermediate E R-807284.Coupling agent for example EDC and DMAP in the presence of with 3-oxo-1-tetradecanoic acid amidation unhindered amina, obtain penultimate product ER-807285.In the presence of excessive triphenylphosphine and proton source (phenyl silane), utilize palladium (0) reagent for example four (triphenylphosphines) close palladium (0) and make allyl group phosphoric acid ester deprotection; obtain (for example to be purified; suitable ion-exchange chromatography condition; subsequently usefulness NaOAc aqueous solution processing) desirable crude product is to obtain desirable compd E 6020.
Should be appreciated that; in the reaction described in the said synthesis route 1,2 and 3 each can utilize described reagent for the synthesis of above-mentioned various types of exemplary intermediates and condition to implement, and perhaps it can use other available reagent, protecting group or initial feed modification.For example, various urea formation conditions, phosphorylation and amine protection/deprotection condition are being known in the art.Usually, referring to March, Advanced Organic Chemistry, the 5th edition, John Wiley ﹠amp; Sons, 2001; " Comprehensive Organic Transformations, a guide to functional group preparations ", Richard C.Larock, VCH publishers, 1999; Its full content is incorporated into by reference at this, and " Protective Groups in Organic Synthesis " third edition Greene, T.W. and Wuts, P.G., Eds., John Wiley﹠amp; Sons, New York:1999, its full content is incorporated into by reference at this.
In a word, the step that the present invention is significantly less with the method than previous report, productive rate is higher provides synthesizing of E6020.Method of the present invention provides title compound with high overall yield and by efficient route.
Following representational example is with helping explain the present invention, neither the scope that is used for also should not be construed as limiting the invention.Certainly, except shown here with describe, various variations of the present invention and many further embodiments thereof are apparent from the full content (comprising the following examples) of the document with in the reference content of this science and technology of quoting and patent documentation for those skilled in the art.The content that be also to be understood that the bibliography that those are cited incorporates to help to explain prior art at this by reference.
The following examples comprise and can be suitable for implementing important Additional Information of the present invention, specific examples and guidance with various embodiments of the present invention and equivalent thereof.
Embodiment
Further explain compound of the present invention and preparation thereof by embodiment, described embodiment illustrates preparation or uses the part of the method for these compounds.But, should be appreciated that, these embodiment do not limit the present invention.Change programme of the present invention is considered as dropping in the scope described herein and required for protection of the present invention.
Further explain compound of the present invention and preparation thereof by embodiment, described embodiment illustrates preparation or uses the part of the method for these compounds.But, should be appreciated that, these embodiment do not limit the present invention.Change programme of the present invention (now known or further develop) is considered as dropping in the scope described herein and required for protection of the present invention.
Utilize the preparation of immunological adjuvant E6020 to illustrate, the following examples comprise the synthetic precursor that utilizes method of the present invention and compound to synthesize the immunological adjuvant compound.
The many analogues that those skilled in the art will recognize that E6020 can be by method of the present invention with by compound preparation of the present invention, include but not limited to United States Patent (USP) 6,551,600,6,290,973 and 6,521, those E6020 analogues of describing in 776, the full content of described document is incorporated into by reference at this.Therefore, should be appreciated that the scope of the present invention that the appended claim of not restricted passage of synthetic method of describing below by the mode of embodiment limits.
General response procedures
Unless stated otherwise, otherwise use the magnetic stirring bar stirred reaction mixture.Inert atmosphere refers to dry argon gas or dry nitrogen.By monitoring reaction to carrying out thin-layer chromatography, proton magnetic resonance (PMR) or high pressure liquid chromatography (HPLC) analyses through the reaction mixture sample of suitably processing.
Below listed abbreviation be used for referred in this some general organic reagents:
ATP: allyl group tetraisopropylphosph-ro phosphoryl diamine
The DMF dimethyl formamide
EA: ethyl acetate
EDC:1-[3-(dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
HBTU:O-benzotriazole-N, N, N ', N '-tetramethyl-urea-phosphofluoric acid ester
The HOBT:1-hydroxybenzotriazole
IPA: Virahol
MTBE: methyl tertiary butyl ether
NaHMDS: hexamethyldisilazane sodium
TBME: t-butyl methyl ether
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
The TsCl toluene sulfonyl chloride
The preparation of embodiment 1:ER-028695
The preparation 1: with 9 minutes times with the ER-028694 (952g in the tetrahydrofuran (THF) (THF) (1041 g) of drying, 5.46mol) be added under 0 ℃, in the stirred solution of the Tosyl chloride (1704g, 8.938mol) among the THF in drying (2408 g) under the nitrogen atmosphere, in the dry 22L reactor.With anhydrous THF (364 g) residual ER-028694 is flushed in the reactor.Triethylamine (1.35Kg, 13.4mol) dropwise is added in the yellow reaction solution of clarification with 19 minutes times, solution becomes is muddy during this period.THF (30g) with drying is flushed to residual triethylamine in the reaction mixture.
After 0 ℃ of lower restir 15 hours 17 minutes, use the hydrochloric acid (2120g) of the 1.0M that slowly adds to react with 36 minutes time end, temperature becomes 5.9 ℃ from 0.1 ℃.Add salt solution (785mL) with times of 3 minutes, continue again to stir 5 minutes, use subsequently THF (0.57Kg) with reaction mixture (~22L) transfer in the treatment reactor of 50L.Organic layer separates (pH=6) with water layer.With the hydrochloric acid (2120 g) of 1.0M and the mixture washing organic layer of salt solution (785mL).And then the mixture of water (2120mL) and salt solution (980mL) washing organic layer.
Organic layer is transferred in the reactor of clean 22L, under nitrogen atmosphere, added subsequently THF (1.6Kg).Under agitation solution is cooled to 0 ℃ (ice-water bath), adds subsequently 10% the NaOH aqueous solution (2.04Kg) with time of 7 minutes, temperature becomes 2.3 ℃ from-0.4 ℃.At the NH that adds 28% with time of 6 minutes
4The OH aqueous solution (935g) afterwards, temperature becomes 12.5 ℃ from 1.9 ℃, stirs the mixture 25 minutes, adds subsequently heptane (1.1Kg).Reaction mixture is transferred in the treatment reactor of 50L with heptane (0.532Kg), fully mixed, leave standstill, discharge water layer (pH 14).With 10% the NaOH aqueous solution (2.04Kg) washing organic layer, then water (2.04Kg) is washed.The solvent (in vacuum chamber (house vacuum)) of evaporation organic layer also makes resistates and heptane (1.1Kg) azeotropic, the orange that obtains clarifying.The material (1.839Kg) of separating is used for next step without being further purified.The analytical data of ER-028695:
1H-NMR (CDCl
3, 400MHz) δ 0.88 (t, J=7.1Hz, 3H), 1.2-1.5 (m, 12H), 1.57 (bs, 1H), 1.6-1.7 (m, 1H), (1.8-1.9 m, 1H), 2.45 (s, 3H), 3.7-3.8 (m, 1H), 4.1-4.2 (m, 1H), 4.2-4.3 (m, 1H), 7.35, (d, J=7.8Hz, 2H), 7.80 (d, J=7.8Hz, 2H).MS-APESI (M+Na) C
17H
28NaO
4S calculated value: 351.16 measured values: 351.23.HPLC:ER-028695:ER-817864 is than being 87.11%:11.71%.
Preparation 2: anhydrous THF (250mL) is added in the stirred solution of Tosyl chloride (161.1g, 0.845mol) under nitrogen atmosphere.Then under 22 ℃ temperature of reactor, add ER-028694 (90.0g, 0.516mol), add subsequently triethylamine (176mL, 1.26mol), the yellow solution that obtains clarifying.Solution becomes is muddy behind the several minutes.Stir after 15 hours 33 minutes, take out 100 μ L samples.GC analyzes and shows that transformation efficiency is 100%.Take out again 100 μ L samples, and extract with 2.0mL water of productive use and 3.0mL heptane.With water of productive use (2.0mL) washing organic layer twice, then use salt solution (2.0mL) washing.The organic layer of vapourisation under reduced pressure gained obtains colorless oil.Colorless oil
1It is 1.00/91.93/7.07 that H-NMR analyzes the ratio that shows ER-028694/ER-028695/ER-817864.
After definite reaction is finished, add the hydrochloric acid soln of 1.0M, temperature becomes 26.8 ℃ from 21.4 ℃, then adds salt solution (74.2mL).Organic layer (~0.6L) with water layer (~0.4L, pH=10) separate, and with the washing of the mixture of 1.0M hydrochloric acid (201mL) and salt solution (74.2mL), use subsequently the mixture of water of productive use (201mL) and salt solution (92.7mL) to wash.Then organic layer is transferred in the clean reactor, under nitrogen atmosphere, added subsequently THF (200mL).Follow to stir solution is cooled to 10 ℃, then with the NaOH aqueous solution (193g) of 2 minutes time adding 10%, keep simultaneously temperature of reaction to be lower than 25 ℃ (temperature becomes 21.3 ℃ from 15.3 ℃).Then add NH with time of 5 minutes
4The OH aqueous solution (88.4g) (observe and postpone heat release) still keeps temperature of reaction to be lower than 25 ℃ (temperature becomes 22.7 ℃ from 15.5 ℃) simultaneously.Under agitation reaction mixture is warming to 20 ℃, continues 15 minutes.(200mL) extracts reaction mixture from water layer with heptane, and the pH of water layer is 14.Then the NaOH aqueous solution (193g) washing organic layer with 10% uses water of productive use (193mL) washing.With heptane (200mL, 29~32 ℃, 4.4 holders) evaporating solvents (at 29~32 ℃, 20 holder) and isolate resistates, the orange that obtains clarifying.The material of separating is used for next step (supposing 100% productive rate) without being further purified.Colorless oil
1It is 0.9/90.9/8.2 that H-NMR analyzes the ratio that obtains ER-028694/ER-028695/ER-817864.KF is 13.0ppm.
The preparation of embodiment 2:ER-806158
Preparation 1: with 33 minutes times with two (trimethylammonium dimethyl silanyl) the acid amides sodium of the 1.0M in THF (3.300Kg) be added under-1 ℃, ER-807277 (1.177 Kg among the THF in drying (10.580 Kg) under the nitrogen atmosphere, in the 22L reactor of drying, 6.642mol) stirred solution in, keeping simultaneously temperature of reaction is-0.8~4.1 ℃.Again at-0.1 ℃ of lower stirred solution after 17 minutes, the thick ER-028695 (1.089 Kg, 3.316mol) in the THF of drying (0.968Kg) is added in the reaction soln with 5 minutes times, maintain the temperature at-0.1~3.9 ℃.THF (0.253Kg) with drying is flushed to residual ER-028695 in the reactor.Final reaction mixture is warming to room temperature, and the orange reaction soln of clarification becomes suspension (in the time of 19 ℃) during this period.After at room temperature stirring 3 hours 31 minutes, the complete reaction mixture is cooled to 0.1 ℃, and with the cold saturated NH of its impouring in the 50L treatment reactor
4In the mixture of the Cl aqueous solution (4.7Kg) and salt solution (1.65L) (heat release, Tmax=16.2 ℃).(2 * 1.0L) then use toluene (3.769 Kg) that residual reaction mixture is flushed in the treatment reactor to water.After stirring the mixture 5 minutes, make reaction mixture sat 5 minutes, and discharge the bottom water layer (pH=9) of gained.Under 30~34 ℃, divide the solvent that evaporates organic layer at internal vacuum chamber.Merge with minimum THF (0.4Kg) rinsing vessel and with washing fluid and product.Shift for convenient, (bath temperature=30~34 ℃) adds toluene (0.4Kg) under heating, so that solid is separated into soup compound.
Under nitrogen atmosphere, thick soup compound is transferred in the 22L reactor of clean drying, under rapid stirring, added heptane (7.503 Kg) under~19 ℃ subsequently.Behind the restir 6 hours 22 minutes, mixture is carried out vacuum filtration (Fisher P5 filter paper, numbering #09-801G), and use respectively 0.99 Kg, 1.02 Kg and 1.01 Kg the heptane wash filter cake (~5.4L) three times.Evaporation merges in vacuum chamber under 30~34 ℃ filtrate and washings obtain muddy orange (1.207 Kg).White filter cake in filter funnel is ER-807277.
Crude product (1.206Kg) is dissolved among methyl tertiary butyl ether (MTBE)/heptane=1/4 (700mL), filter by medium size frit filter funnel, then use MTBE/ heptane=1/4 (300mL) flush cake, the yellow filtrate that obtains clarifying.With being transferred to~flow (~25 pounds/square inchs of solvent pressure) of 840mL/ minute, thick ER-806158 solution is loaded into through the silicagel column regulated in advance (with MTBE (10.46 Kg), then use on the Biotage 150L that MTBE/ heptane=1/4 (3.140 Kg/11.606 Kg) processes (5.62 Kg, the post of void volume=7.07L)).Behind the loading, with MTBE/ heptane=1/4 (0.148 Kg/0.547 Kg) flushing post, use subsequently MTBE/ heptane=1/4 (2.09Kg/7.740Kg), MTBE/ heptane=2/3 (2.094Kg/2.904Kg), MTBE/ heptane=7/3 (3.661Kg/1.448Kg) and use at last MTBE (40.298Kg) wash-out.In whole chromatographic process, collected the approximately fraction of 350mL.The concentrated fraction that contains product that merges is also used heptane (0.540 Kg) azeotropic drying, subsequently under 33 ℃ vacuum chamber inner drying 1 hour 13 minutes, the orange that obtains clarifying (0.793 Kg, 71%), purity are 98.32 area %.The crystallization of ER-806158
The ER-806158 of the purifying of 2.376 Kg is dissolved in the heptane (8.121Kg), and under nitrogen atmosphere, transfers in clean, the dry 22L reactor, stir subsequently.Little by little the yellow solution of clarifying is cooled to-15 ℃ with per 0.5 hour~4 ℃.The white suspension of gained is-15 ℃ of lower restir 1 hour, and vacuum filtration on the filter funnel of cooling and filter paper makes nitrogen blanket cover filter cake simultaneously subsequently.Cold heptane (12.3 ℃, 1.387 Kg) with above-mentioned filtration washs desirable solid, and makes filter cake remain on vacuum lower 14 hours 13 minutes (T=14.9~18.8 ℃), makes simultaneously nitrogen blanket cover the top of solid.Merge mother liquor, washings and in reactor the solvent of the residual ER-806158 of dissolving with recycling.
Obtain: 2.068Kg, 87.0% productive rate
The analytical data of ER-806158
● purity: 99.84wt/wt%
● chiral purity: 99.72%e.e.
●KF:0.21%
● heptane: 268ppm
●
1H-NMR(CDCl
3)δ0.88(t,J=6.9Hz,3H),1.2-1.6(m,12H),1.6-1.7(m,1H),1.7-1.8(m,1H),3.21(bs,1H),3.6-3.7(m,3H),3.7-3.8(m,2H),3.5-3.6(m,2H),4.2-4.3(m,1H),4.5(m,2H),7.42,(t,J=7.6Hz,2H),7.49,(dd,J=6.9,7.8Hz,1H),7.95(d,J=7.3Hz,2H)。
● ultimate analysis (EA): C
30H
59NO
6Calculated value: C, 72.04; H, 9.37; N; 4.20 measured value: C, 71.83; H, 9.30; N, 4.08.
● fusing point (DSC) beginning, 26.7 ℃; Maximum, 29.5 ℃.
Preparation 2: suppose 100% productive rate, calculate the amount (mol) that is used in the ER-028695 in the reaction according to the amount of the initial ER-028694 in the step 2 that is used in embodiment 1.Under nitrogen atmosphere, ER-807277 (178.3g, 1006mmol) is added in the 5L reactor of clean drying.Follow to stir to add dry THF (1.8L) with the yellow solution of preparation clarification, and this solution is cooled to 0 ℃.Add NaHMDS/THF (1.0M, 553mL) with times of 20 minutes, and temperature of reaction is remained on be less than or equal to 5 ℃ (3.8~1.3 ℃).Then stirred solution 10 minutes is cooled to-5 ℃.Under nitrogen atmosphere, thick ER-028694 (being calculated as 165g, 503mmol) is transferred in the dry clean flask orange solution that obtains clarifying along with stirring with dry THF (165mL, 1vol.).Then with time of 6 minutes ER-028695/THF solution is added in the reaction soln, temperature becomes 0.4 ℃ from-3.2 ℃.THF (40mL) with drying is flushed to residual ER-028695 in the reactor, and in warm water bath (23 ℃) reaction mixture is warming to room temperature.In warm process, the orange reaction soln of clarification becomes suspension.After 1.75 hours, take out sample (10 μ L) 18.7~21.3 ℃ of lower stirrings, be added among the 1.0mL MeCN, and filter by the syringe-type strainer of 2 μ m, obtain the filtrate of colourless clarification.It is 98.2% that HPLC analysis (TM-779) detects transformation efficiency.After at room temperature stirring 3 hours fully, HPLC analyzes and shows that transformation efficiency is 99.5%.With saturated NH
4The Cl aqueous solution (0.66L) once all adds (heat release, 18.9~26.0 ℃), then adds water of productive use (0.30L), salt solution (0.25L) and toluene (0.66L).Adding rear continuation stirred 5 minutes.Under 29~32 ℃ under reduced pressure part evaporate the top organic layer solvent (~2.6L), obtain soup compound (481.7g), discharge the water layer (~1.4L, pH=11) of bottom.
Under nitrogen, soup compound is transferred in the dry clean 5L reactor.At room temperature under rapid stirring, add heptane (1.65L), continue to stir 14 hours.Mixture is carried out vacuum filtration (medium size filter paper), usefulness heptane (0.33L) washing gained filter cake (~0.52L), and the filtrate of collection yellow (~2.8L).Vapourisation under reduced pressure solvent (29~32 ℃) obtains orange oily matter (177.9g).
Crude product (177.9g) is dissolved in TBME/ heptane=1/4 (178mL), and with the flow of adjusted~170mL/ minute (~18 pounds/square inchs solvent pressure) be loaded into TBME (2.1L), (834 g are on the post of void volume=1.05L) then to use the Biotage 75L silica gel that TBME/ heptane=1/4 (3.15L) regulates.Collect fraction 1~2 (each level is divided into~350mL).Behind the loading, with TBME/ heptane=1/4 (178mL) flushing post and with TBME/ heptane=1/4 (2.1L) wash-out, collect fraction 2~8; With TBME/ heptane=2/3 (1.05L) wash-out, collect fraction 8~11; With TBME/ heptane=7/3 (1.05L) wash-out, collect fraction 11~14; And with TBME (8.4L) wash-out, collect fraction 15~39.Analyze collected fraction (TLC, silica gel F254; Moving phase, TBME; Visualization, UV and aubepine solution), merge the product that contains the fraction (14~35) that does not have the ER-807277 pollution.Make solvent evaporation (29~32 ℃, 80 holders) with heptane (29~32 ℃, 10.3 holders), the orange that obtains clarifying (114.4g), it solidifies when cool to room temperature.HPLC analyzes (TM-779) and detects 96 area %.
Under nitrogen atmosphere, follow in the clean reactor that stirs the drying of using warm (29~32 ℃) orange solids (114.4g, 1wt) of heptane (572mL) and transferring to 1L.Solution is cooled to 14 ℃, stirred 0.5 hour, and brilliant as planting with ER-806158 crystal (0.112g).Continue to stir 0.5 hour, can see solid particulate during this period.Reaction mixture is cooled to gradually-10 ℃ (per 0.5 hours 4 ℃), further is cooled to-15 ℃, continue simultaneously to stir 1 hour.(~cold medium size the filter funnel that 200mL) obtains by this funnel vacuum filtration reaction mixture, is used cold heptane (approximately-20 to-15 ℃) washing subsequently by cold (~-20 ℃) heptane.Continued to apply vacuum 1.5 hours, and nitrogen blanket is applied to the top of filter cake.Then the white coarse granular solids (98.4g, 0.295mol) of gained is transferred in the bottle.Analytical results shows: wt/wt%, 99.95; Purity, 99.68, residual heptane, 19.1ppm; KF, 1.04%.DSC begins melting when showing 27 ℃.Chirality HPLC analyzes (TM-573) and detects 99.8 area %.
The preparation of embodiment 3:FR-819059
The preparation 1: with DMAP (51 g, 0.417mol) join under the nitrogen atmosphere in clean dry 22L flask at dry methylene chloride (CH
2Cl
2) N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (904 g in (3710g), 4.176 mol), lauric acid (purifying, 881 g, 4.398mol) and in the stirred solution of ER-806158 (1400 g, 4.198 mol).Stir after 1 hour 13 minutes, reaction mixture becomes light slightly turbid yellow solution, and temperature of reaction reaches 26.7 ℃ maximum.After 6 hours 34 minutes, find to react and finish 98.9%, this moment is with other N-(3-dimethylamino-propyl)-disposable whole addings of N '-ethyl-carbodiimide hydrochloride (303 g, 1.581mol).At room temperature amount to and stir after 20 hours 50 minutes, MeOH (5566g) is once all joined (little heat absorption, T in the yellow reaction suspension
Min=17.1 ℃).CH is removed in partial solvent evaporation (in vacuum chamber, 29~32 ℃)
2Cl
2(3.71Kg), use subsequently heptane (2 * 2.86kg ea.) extraction of equal portions.Evaporation heptane extraction liquid (in vacuum chamber, 30~35 ℃) also uses heptane (0.75Kg) azeotropic drying.
Product (2.192Kg) is dissolved in the heptane (3.00Kg), and is loaded on the silicagel column (with MTBE/ heptane=pretreated Biotage 150L silica gel (5.62Kg) of 1/1 (15.0Kg)).With MTBE/ heptane=1/1 (31.3Kg.) the flow eluted product with adjusted~0.84L/ minute (solvent pressure=22 pounds/square inch), collect approximately 350mL elutriant/fraction.Merge the fraction contain product and concentrate drying and vacuum-drying (16 ℃, in vacuum chamber, 16 hours 13 minutes), obtain the ER-819059 (2.102Kg, 86.4% productive rate) as the light yellow oil of clarification.
The analytical data of ER-819059
● HPLC analyzes: 99.76 area %.
●KF:0.36%
● heptane: 725ppm
●
1H-NMR(CDCl
3)δ0.881(t,J=7.1Hz,3H),0.884(t,J=6.9Hz,3H),1.2-1.3(m,26H),1.5-1.6(m,2H),1.6-1.7(m,2H),1.8-1.9(m,2H),2.28(t,J=7.6Hz,2H),3.4-3.6(m,3H),3.69(dd,J=3.7,9.6Hz,1H),4.3-4.6(m,3H),5.0(m,1H),7.43,(t,J=7.6Hz,2H),7.51,(dd,J=6.0,7.3Hz,1H),7.95(d,J=6.0Hz,2H)。
● MS-APESI (M+H) C
32H
54NO
4Calculated value: 516.41 measured values: 516.48
● TLC:(silica gel F254): MTBE/ heptane=1/1; The R of ER-819059
f=0.51
The preparation 2: under nitrogen atmosphere with N-(3-dimethylamino-propyl)-N '-ethyl-carbodiimide hydrochloride (1.49g, 7.77mmol), ER-806158 (2.00g, 6.00mmol), DMAP (0.07g, 0.59mmol) and dodecylic acid (1.44 g, 7.19mmol) be added in the dry 50mL flask.Then under agitation add dry methylene dichloride (6.0mL).At room temperature continue to stir, until obtain slightly turbid solution.Stir after 16 hours, take out sample (10 μ L), and join among the 1.5mLMeCN.It is 95.1% that HPLC analysis (TM-780) detects transformation efficiency.And then the N-(3-dimethylamino-propyl) of the other amount of adding-N '-ethyl-carbodiimide hydrochloride (0.307g, 1.60mmol).Restir 8h (24 hours altogether) takes out the second sample (10 μ L) and also analyzes as previously mentioned afterwards.It is 99.6% that HPLC analysis (TM-780) detects transformation efficiency.Continue again to stir 15 hours (39 hours altogether), take out the 3rd sample and analysis this moment.HPLC (TM-780) analyzing and testing is 99.96% to transformation efficiency.Then add saturated NaHCO
3The aqueous solution (10mL), salt solution (10mL) and heptane (10mL) continue to stir 0.5 hour simultaneously.Observe relatively poor milk sap.Then add heptane (10mL), and fully mix, but there is no and improve this milk sap.Then, add MeOH (3.0mL) and fully mix, but it also there is no and improves this milk sap.Composition was left standstill 0.5 hour, discharge the water layer of the emulsus that forms in the bottom.With TBME (20mL) aqueous layer extracted, leave standstill and approximately discharge the bottom water layer after 15 minutes.The TLC of water layer analyzes (TLC, silica gel F254; Moving phase, TBME; Visualization, UV and aubepine solution) detect a large amount of products.Use again TBME (20mL) aqueous layer extracted, and merge organic layer.The yellow oil (3.35g) that solvent evaporation (29~32 ℃, 7.5 holders) obtains clarifying.
Crude product (3.35g) is dissolved in TBME/ heptane=1/1 (12mL), and is loaded into that (8.99 g are on the post of void volume=11.3mL) with the pretreated Biotage 12M silica gel of TBME/ heptane=1/1 (36mL).With adjusted~12mL/ minute flow eluted product, collect 15 fractions (each~6mL).Analyze collected fraction (TLC, silica gel F254; Moving phase, TBME/ heptane=1/1; Visualization, UV and aubepine solution), and merge the fraction (3~15) that contains product.The colorless oil (3.03g) that solvent evaporation (29~32 ℃, 8.3 holders) obtains clarifying.HPLC analyzes (TM-780) and detects 99.18 area %.Do not carry out water treatment owing to relatively poor emulsification.
The preparation of embodiment 4:ER-819120
Under nitrogen atmosphere, ER-819059 (3.03 g, 5.87mmol, 1wt) and 10%Pd/C (0.303 g, 0.28mmol) are added in the flask of the clean 50mL that IPA (20.2mL, 6.67vol.) is housed.This flask of at room temperature under rapid stirring, finding time, and purge with hydrogen (hydrogen pressure remains on 0.04 bar).This finds time-and purge repeats twice again.HPLC analysis monitoring reaction by different samples.After reaction was finished, approximately 3.5 days, the flask of finding time was also used nitrogen purging three times.Filter the mixture of gained by the syringe-type strainer of 0.2-μ m, and (2 * 4.0mL) wash with IPA.Then the filtrate that merges colourless clarification, crude product/IPA solution is used for next step reaction (do not have purifying, suppose 100% productive rate).
The preparation of embodiment 5:ER-819302
Calculate the amount (mol) of ER-819120 according to the initial ER-819059 of abovementioned steps.
(ER-8189120 of 2.52g equivalent, 5.87mmol is in~31.5mL) the 50mL flask under agitation tert-Butyl dicarbonate (1.30g, 5.96mmol) once all to be joined the ER-819120 that is equipped with in IPA under nitrogen atmosphere.By HPLC (sample preparation: sample 15 μ L, and being added among the MeCN of 1.0mL) and TLC (TLC, silica gel F254; Moving phase, MeOH/CH
2C
l2/NH
4OH=10/89/1; Visualization, aubepine solution or ninhydrin solution) the monitoring reaction.TLC only detects less ER-819120 spot.Add more tert-Butyl dicarbonate (0.20g, 0.92mmol).TLC analyzes and does not observe improvement.Solvent evaporation (29~32 ℃, 10 holders) obtains colourless clarification oily matter (3.21 g).
With TBME/ heptane=1/1 (36mL, 3 v.v.) treatments B iotage 12M silica gel (8.99 g, the post of void volume=11.3mL).Flow is adjusted into~12mL/ minute.After crude product (3.35g) is dissolved in TBME/ heptane=1/1 (12mL), it is loaded on the described post, and with TBME/ heptane=1/1 (70mL) wash-out.Collect 15 fractions (each~6mL) and analyze (TLC, silica gel F254; Moving phase, TBME/ heptane=1/1; Visualization, UV and aubepine solution).Merge the product in the fraction (3~15).Solvent evaporation (29~32 ℃, 8.3 holders) obtains colourless clarification oily matter (3.03g).
The alternative preparation of embodiment 6:ER-819302
With 10%Pd/C (99g=flask 1,102g=flask 2) is added to being divided in equal size among two parts the ER-819059 (1.970 Kg, 3.82mol) in two clean 12L reactors that Virahol (IPA) (being respectively 4.647Kg) is housed.Then (0.79 bar) flask of finding time uses hydrogen (0.05 bar) to purge three times, stirs simultaneously.Reaction was the lower maintenance of the nitrogen atmosphere (0.04 bar) of room temperature 7 days 16 hours, and after this find time (in vacuum chamber) reacts and purge three times with nitrogen, to remove the excessive hydrogen of all traces, is cooled to 0 ℃ subsequently under nitrogen atmosphere.
In two independent flasks, under nitrogen atmosphere, tert-Butyl dicarbonate (being respectively 434g, 1.99mol and 438g, 2.01mol) is dissolved among the anhydrous THF (being respectively 203g).Be added in each flask with the ER-819120 reaction mixture of 5 minutes times with cooling.With anhydrous THF (being respectively 40g) residual reactant is flushed in the reaction mixture.Find that reaction is (4.5 to 10.1 ℃) of heat release and observes venting.Reaction is warming to room temperature also to be continued to stir to spend the night.Merge the reaction finish and filter with diatomite 545 (1.143Kg is loaded on the strainer of Fisher P524cm), under nitrogen blanket, wash with IPA (3.091Kg).With residue and the filtration in IPA (1.417 Kg) the flushing reactor, use subsequently IPA (13.46Kg) flushing filter bed.Use again twice of IPA (being respectively 4.573Kg and 6.360Kg) flushing filter bed.
The concentrated filtrate that merges is used heptane (7.529Kg) azeotropic, the colorless oil (2.452Kg that obtains clarifying subsequently; Purity is 70.57 area %).Crude product is equally divided into four parts of purifying.
With thick ER-819302 (611g, 1wt) be dissolved in heptane (613g, 1wt), and be loaded into Biotage 150L silicagel column [(5.620Kg), utilize 700mL/ minute flow, with MTBE (10.48Kg), then use heptane (15.51 Kg) to process] on.Wash the ER-819302 that remains on the post with heptane (340g, 0.56wt).With 15%MTBE/ heptane (7.102Kg/36.994Kg), then use MTBE (15.72 Kg) wash-out post, collect the fraction of every part of about 3L this moment.Use the individually thick ER-819302 of the remaining three equal parts of chromatography of identical method.The desirable fraction of concentrated merging from four parts of purified products and with heptane (0.5Kg) azeotropic drying obtains the ER-819302 (1.9135Kg as the colorless oil of clarification; Productive rate under 97.86 area % purity is 94.6%).
The analytical data of ER-819302-00
●
1H-NMR(CDCl
3)δ0.89(t,J=6.9Hz,6H),1.2-1.3(m,26H),1.46(s,9H),1.5-1.7(m,4H),1.7-1.8(m,1H),1.8-1.9(m,1H),2.30(t,J=7.6Hz,6H),3.3-3.4(m,1H),3.48(td,J=6.9,9.6Hz,1H),3.5-3.6(m,2H),3.69(td,J=6.1,7.1Hz,1H),3.76(d,J=8.2Hz,2H),5.0-5.1(m,1H),5.2(bs,1H)。
● MS-APESI (M+Na) C
30H
59NNaO
6Calculated value: 552.42 measured values: 552.52
●KF=0.30%
● heptane=6034ppm; MTBE=does not detect.
The preparation of embodiment 7:ER-819344
The preparation 1: under nitrogen atmosphere at room temperature with the trifluoroacetic acid pyridine
(30.9g, 0.160mol) once all is added at anhydrous CH
2Cl
2In the stirred solution of the Diisopropylamine (22.4mL, 0.160mol) (200mL), little heat release.In case reaction mixture is got back to room temperature, just add allyl group tetraisopropylphosph-ro phosphoryl diamine (51.1mL, 0.160mol), stirred subsequently 10 minutes.Use anhydrous CH
2Cl
2(300mL) with ER-819302 (84.4g, 0.159mol) azeotropic drying several times, until determine that water-content is lower than 60ppm.ER-819302 is dissolved in methylene dichloride (300mL) afterwards, lentamente solution is added to above-mentioned pyridine
In the reaction mixture, make temperature of reaction remain on 20~30 ℃, use subsequently other methylene dichloride (100mL) flushing from the resistates of reaction vessel.
When the formation of reaction intermediate ER-820116 fully when (2 hours), reaction mixture is cooled to 0 ℃, dropwise add subsequently acetic acid (18.2mL, 0.320mol), make temperature of reaction remain on 0~15 ℃.With the trifluoroacetic acid pyridine
(11g, 0.056mol) is added in the reaction mixture, and stirs the reaction 10 minutes of gained, afterwards immediately with the disposable adding of ER-222581 (46.5g, 0.164mol).At room temperature stirred reaction mixture is 2 hours, then mixture is cooled to 0 ℃, dropwise adds the hydrogen peroxide (49mL, 0.480mol) in water of 30wt.%, makes final temperature of reaction remain on 0~10 ℃ (initial exotherm is very strong).Reaction mixture is warming to room temperature, and restir 30 minutes, reaction mixture is cooled to 0 ℃ afterwards.By so that temperature of reaction remains on 0~10 ℃ adding speed adds lentamente 10wt.% aqueous solution of sodium bisulfite (3.5L) and finish final reaction mixture.The reactant that finishes is warming to room temperature and stirring, until be used for the negative superoxide test (30 minutes) of two subsequent layer.
Mixture with MTBE (2.0L) dilution gained stirred 10 minutes, then transferred in the processing vessel.Layer is separated and with 5% NaHCO
3The aqueous solution (2.0L) and salt solution 1: 1 mixture in water washs organic layer once respectively separately.Water layer with MTBE (1L) reextraction merging.With the dry organic layer that merges of anhydrous sodium sulphate (100g), filter and concentrate, use the MTBE azeotropic drying, obtain ER-819344 (146.6 g, productive rate are that the purity of 97%, HPLC is 91%).
The data analysis of ER-819344
●
1H-NMR(CDCl
3)δ0.85-0.90(m,6H),1.20-1.36(m,26H),1.40-1.65(m,4H),1.44(s,9H),1.70-1.83(m,2H),2.27(t,J=7.6Hz,2H),3.37-3.57(m,6H),3.90-4.00(m,1H),4.03-4.10(m,1H),4.11-4.24(m,3H),4.35-4.40(m,2H),4.50-4.60(m,2H),4.94-5.0(m,1H),5.05-5.15(m,1H),5.22-5.27(m,1H),5.30-5.40(m,1H),5.85-6.0(m,2H),6.01-6.05(m,1H),7.30(dd,J=7.3,7.8Hz,2H),7.40(dd,J=7.3,7.8Hz,2H),7.61(d,J=7.8Hz,2H),7.76(d,J=7.3Hz,2H)。
●
31P-NMR (CDCl
3, not calibration) and 0.172,0.564 (two diastereomers)
● MS-APESI (M+Na) C
50H
79N
2NaO
11P calculated value: 937.53 measured values: 937.65.
Preparation 2: ER-819302 (1wt.) is dissolved in the anhydrous methylene chloride (3vol.).If the total amount of water is more than or equal to the ER-819302 of 0.7mol.%, as pass through K
fDetermined, so by utilizing evaporating solvent to expel water so that reduced water content is arrived gratifying level.
Anhydrous methylene chloride (2vol.) is installed in the dry reactor, add subsequently Diisopropylamine and trifluoroacetic acid pyridine
(1 equivalent) (before adding in bath with the control heat release).Stirred solution, and in bath, temperature is transferred to 20~25 ℃.Then allyl group tetraisopropylphosph-ro phosphoryl diamine (1 equivalent) is added in the solution, stirred subsequently 5 minutes.Then be added in the solution with the dichloromethane solution of controlled adding speed with ER-819302, keep simultaneously temperature of reaction to be lower than 30 ℃ (with the dichloromethane rinse of 1vol.).By TLC (MTBE/ heptane/Et
3N=40/60/1) and HPLC (TM is by taking out the 30ul reaction mixture and preparing sample with the 1ml dilution in acetonitrile) monitor reaction process.When the ratio of ER-819302:ER-820116 during greater than 95: 5, reaction is finished, and this occured in 2 hours usually.After intermediate E R-820116 forms, reaction mixture is cooled to 0~10 ℃, and adds acetic acid with the adding speed that keeps temperature of reaction to be lower than 15 ℃.
With the trifluoroacetic acid pyridine
(0.4 equivalent) is added in the reaction mixture, adds subsequently ER-222581 (1 equivalent).At room temperature stirred the mixture approximately 20~30 minutes, until white suspension becomes settled solution.By TLC (MTBE/ heptane/Et
3N=40/60/1) and HPLC (TM is by taking out the 30ul reaction mixture and preparing sample with the 1ml dilution in acetonitrile) monitor reaction process.After reaction is finished, approximately 1.5 or 2 hours, reaction mixture is cooled to-5~0 ℃.
Then the hydrogen peroxide in water (3 equivalent) with 30wt.% is added in the reaction mixture, keeps simultaneously temperature of reaction to be lower than 5 ℃.Reaction mixture is warming to room temperature, then stirred 30 minutes.Afterwards it is cooled back-5~0 ℃, and add the 10wt.% aqueous solution of sodium bisulfite, keep simultaneously temperature of reaction to be lower than 5 ℃.After adding bisulfite solution, again reaction mixture is warming to room temperature, then stirred 30 minutes.Continue to stir, until reaction mixture is indicated negative findings in the superoxide test strip.
Methyl tertiary butyl ether is joined in the reaction, and stirred 10 minutes.Then transfer to reaction mixture in the processing vessel and layer is separated.Contain product if show water layer, then with the methyl tertiary butyl ether water layer of stripping.Sodium bicarbonate aqueous solution washing organic layer with 5%, then use half salt water washing (if water layer is muddy, then be necessary to strip with methyl tertiary butyl ether), concentrated organic layer (if it becomes emulsus oil, then using MTBE charging and vacuum filtration).Analyze thick ER-819344 with HPLC and HNMR.The test of maximum-norm obtains 84.4g ER-819302, and productive rate is 97%, shown in HPLC.
The preparation of embodiment 8:ER-819385-00
At room temperature the dimethylamine with the 2.0M in THF (8.5mL, 17.0mmol) is added in the stirred solution of the ER-819344 (1.56g, 1.70mmol) in THF (1.5mL), and stirred reaction mixture 2 hours.The concentrated reaction mixture of finishing is also used twice of MTBE (15mL) azeotropic drying crude product.The product of gained is dissolved in MTBE (30mL), and washs with salt solution (7.5mL).Final organic layer is concentrated into drying, and with MTBE (15mL) azeotropic once, obtains desirable, some unsettled ER-819385, it is used for next step without purifying.
Preparation 2: ER-819344-00 (1.56 g, 1.70mmol) is dissolved among the THF (1.5mL), and at room temperature is added in the dimethylamine commercial solution (2.0M, 8.5mL) in THF, and stirred 2 hours.Carry out TLC and analyze, show the ER-819344 completely consumed.U.V. lamp and p-anisaldehyde spot are used as the visualization technology.Then remove volatile matter by the rotary evaporation technology.(2 * 15mL) azeotropic crude products are dissolved in it MTBE (30mL) and afterwards with salt solution (7.5mL) washing, to remove the amine (for example, dimethylamine, thanomin) of any residual low MW with MTBE.Do not obtain milk sap, because layer easily separates.The pH of water layer is~10 after this washing.Organic layer is concentrated into drying, and also (1 * 15mL) azeotropic is to obtain desirable amine monomers ER-819385-00 with MTBE.
The preparation of embodiment 9:ER-819409-00
Preparation 1: with saturated NaHCO
3Solution (12mL) is added at CH
2Cl
2In the stirred solution of thick ER-819385 (15mL) (calculated value 1.18g, 1.70mmol).The mixture of gained is cooled to 0 ℃, dropwise adds subsequently 20% the phosgene in toluene (465 μ L, 0.935mmol).Reaction is warming to room temperature, stirred 1 hour, then be cooled to before 0 ℃ at the phosgene solution (210 μ L, 0.425mmol) that adds second part 20%.Final reaction mixture is warming to room temperature, and stirring is spent the night.Add water (15mL).Behind the restir 30 minutes, layering 45 minutes is transferred in the separating funnel in the reaction that finishes.Use CH
2Cl
2(30mL) aqueous layer extracted, and the organic layer of concentrate drying merging.With MTBE/ ethyl acetate (EtOAc) (1: 1,50mL) the thick oily matter of azeotropic drying, be dissolved in the EtOAc/ heptane (1: 1,50mL), and filter to remove salt at the frit funnel.At silica gel (12g) with 2.5%MeOH/ ethyl acetate (50mL), with 3.8%MeOH/ ethyl acetate (50mL) and come the purification of crude product with 5.6%MeOH/ ethyl acetate (100mL) wash-out at last, to obtain the ER-819409 (984mg, productive rate are 82%) as the colorless oil of clarification.
Preparation 2: ER-819385-00 (1.70mmol, thick material) is dissolved in CH
2Cl
2(15mL) and be added to saturated NaHCO
3In the solution (12mL).The mixture of gained is cooled to 0 ℃, and dropwise joins in the phosgene commercial solution (465 μ L, 0.55 equivalent) in toluene.Under stirring in 1 hour, reaction is warming to room temperature.TLC (10%MeOH/CH
2Cl
2) and the p-anisaldehyde analysis be used for manifesting reaction product, show still to have a large amount of initial feed.Therefore reaction is cooled to 0 ℃, in order to add 20% phosgene solution (210 μ L, 0.25 equivalent) for the second time.After the adding, temperature of reaction is warming to room temperature lentamente.TLC after 1 hour analyzes and still shows initial feed, but does not show the sign of decomposition.Then make the reaction standing over night, stir simultaneously.The TLC of second day the analysis showed that and still has initial feed, decomposes but also show baseline.At room temperature be added to water (15mL) in the reaction product and stirred 30 minutes.Mixture is transferred in the separating funnel, before separating described layer, they were left standstill 45 minutes.Use CH
2Cl
2(30mL) aqueous layer extracted merges organic layer and concentrate drying.The TLC of the organic layer of water layer and merging analyzes the existence that does not show the amine initial feed, shows that reaction is carried out fully in treating processes.
With the thick oily matter of MTBE/EA azeotropic, be dissolved in again~1: 1 the EA/ heptane of 50mL, and filter to remove salt at the frit funnel.At SiO
2Upper this material of purifying of post (50%EA/ normal heptane, 100%EA, then 5-10%MeOH/EA), the desirable urea ER-819409-00 that exists with colorless oil to obtain 984mg.The productive rate that this expression begins altogether from the Fmoc deprotection is 82%.Material balance is the baseline material that forms in the stirred overnight process of urea formation stages.
Synthesizing of the dihydroxyl urea of embodiment 10:ER-819409-00
With the speed that keeps temperature of reaction to be lower than 30 ℃ Diisopropylamine (78.7mL, 0.561mol) is added to trifluoroacetic acid pyridine in anhydrous acetonitrile (348g)
In the stirred solution of (108g, 0.533mol).After making the reaction cool to room temperature, add allyl group tetraisopropylphosph-ro phosphoryl diamine (179mL, 0.561mol) (observing a little heat absorption, then heat release), restir is 10 minutes subsequently.Then so that remaining on 20~30 ℃ adding speed, temperature of reaction is added in ER-819302 (283.2 g, 0.5345mol in the anhydrous acetonitrile (453mL); Heptane with 800mL is expelled in advance).Behind the restir 30 minutes, reaction mixture is cooled to 0 ℃, slowly adds subsequently acetic acid (64mL, 1.1mol), keep simultaneously temperature of reaction to be lower than 25 ℃.Make at room temperature balance of reaction mixture.With the trifluoroacetic acid pyridine in acetonitrile (200mL)
(103g, 0.533mol) is added in the reaction mixture.Adding the trifluoroacetic acid pyridine
Afterwards, add immediately ER-812978 (40g, 0.27mol), use subsequently acetonitrile (50mL) flushing.At room temperature stirred reaction mixture is 18 hours, it is cooled to 0 ℃ afterwards, slowly is added in subsequently the hydrogen peroxide (140mL, 1.37mol) of the 30wt.% in the water, makes temperature of reaction remain on 0~24 ℃ (strong heat release during beginning).Final reaction mixture restir 30 minutes is subsequently so that temperature of reaction remains on 0~18 ℃ speed adding 20wt% aqueous solution of sodium bisulfite (3000g).Reaction mixture is warmed to room temperature and stirring, until the superoxide test provides negative findings.
In processing vessel with the reaction mixture of MTBE (3000mL) dilution gained and stirred 15 minutes.After layer is separated, with 10% sodium bicarbonate (NaHCO
3) aqueous solution (3500mL), then use the 30%NaCl aqueous solution (2000mL) washing organic layer.With MTBE (3000mL) reextraction brine layer three times.The concentrated organic layer that merges also uses TBME/ heptane=1/1 (1.4L) to expel twice.Resistates is dissolved in MTBE (735g), and by Celite pad (150g) filtering suspension liquid, uses subsequently MTBE (300mL) washing container and filter pad three times.Concentrate drying filtrate obtains the slightly turbid oily matter of 363.4g.Utilize adjusted~800mL/ minute flow with TBME/ heptane=7/3 (400mL) with thick ER-819302 dissolving and be loaded on the pretreated silicagel column [the Biotage 150L that processes with MTBE/ heptane=7/3 (15Kg) (5.62Kg, the post of void volume=7.07L)].Behind the loading, be loaded on the post with TBME/ heptane=7/3 (500mL) residual ER-819302 of flushing and with washing fluid.With MTBE/ heptane=7/3 (26Kg), then use MTBE/ heptane/MeOH=70/25/5 (21.8Kg/7.18 Kg/1.7Kg) wash-out post.In this process, altogether collect 36 fractions.The concentrated fraction that contains product that merges is also used heptane (8L) azeotropic drying, subsequently at the vacuum chamber inner drying, obtains the oily matter that purity is 92.69 area % (281g, 79%).
The analytical data of ER-820116
●
1H-NMR(CDCl
3)δ0.870(m,6H),1.176(d,J=8.0Hz,12H),1.254-1.282(b,28H),1.428(b,9H),1.528(b,2H),1.603(b,2H),1.790(m,2H),2.265(t,J=7.0Hz,2H),3.431(m,2H),3.481(m,2H),3.600(m,2H),3.751(b,2H),3.847(b,1H),3.847-4.208(m,2H),4.950(b,1H),5.126(d,J=10Hz,1H),5.286(dd,J=17Hz,J’=1.5Hz,1H),5.898-5.989(m,1H)
●
31P-NMR (CDCl
3, not calibration) and 148.449 and 148.347 (two diastereomers)
● MS-APESI (M+Na) C
39H
78N
2O
7P calculated value: 717.55 measured values: 717.66.The analytical data of ER-821843
●
31P-NMR (CDCl
3, not calibration) and δ 139.832,139.868,140.170,140.327 (4 diastereomers)
● MS-APESI (M+Na) C
30H
59NNaO
6Calculated value: 552.42 measured values: without mass-spectrometric data
The analytical data of ER-819409
● MeOH: do not detect
● MTBE: do not detect
●MeCN:185ppm
● heptane: 1718ppm
●
1H-NMR(CDCl
3)δ0.88(t,J=6.9Hz,12H),1.20-1.37(m,52H),1.44(s,18H),1.45-1.72(m,8H),1.76-1.85(m,4H),2.28(t,J=7.6Hz,4H),3.38-3.58(m,12H),3.85-3.97(m,2H),3.98-4.20(m,8H),4.53-4.58(m,4H),4.95-5.0(m,2H),5.18-5.28(m,2H),5.26(dd,J=1.4,10.5Hz,2H),5.37(dd,J=0.9,16.9Hz,2H),5.62-5.85(m,2H),5.87-5.99(m,2H)。
● MS-APESI (M+Na) C
71H
136N
4NaO
19P
2Calculated value: 1433.92 measured values:
1433.98。
The preparation of embodiment 11:ER-807284-00
Preparation 1: under nitrogen atmosphere with time of 10 minutes lentamente with methylsulfonic acid (13.8g, 144mmol) at CH
2Cl
2Solution (140mL) is added at dry CH
2Cl
2In the stirred solution of ER-819409 (120mL) (40.25 g, 28.51mmol), keep simultaneously temperature of reaction to be lower than 20 ℃.Reaction mixture is warming to 20 ℃, stirred subsequently 15 hours, until determine that intermediate reaction is complete.The reaction mixture of gained is cooled to 0 ℃ and with 5 minutes time adding diisopropylethylamine (27.5mL, 158mmol).Again after stirring 5 minutes under 0 ℃, with 1-(3-dimethylamino-propyl)-disposable adding of 3-ethyl-carbodiimide hydrochloride (32.55g, 170mmol).Reaction mixture is at 0 ℃ of lower the stirring 12 minutes, subsequently disposable adding ER-028699 (20.6 g, 85.0mmol).The reaction mixture of gained is warmed to room temperature subsequently 0 ℃ of lower stirring 2 hours, continues 30 minutes, determines during this period to react completely.
[(351g silica gel is with MTBE (1L), then use CH at pretreated Biotage 75M silicagel column with the flow that is adjusted to 150~200mL/ minute
2Cl
2(2L) pre-treatment] 1/4th (105 g) of the reaction mixture finished of upper wash-out.Use continuously 1% ethanol (EtOH)/CH
2Cl
2(900mL), use 3%EtOH/CH
2Cl
2(900mL), use at last 6%EtOH/CH
2Cl
2(2250mL) wash-out post, simultaneously collection~150mL/ fraction.Merge the desirable fraction of product, concentrated (in the vacuum chamber, 30~35 ℃) of containing and also use heptane (100mL) azeotropic three times, obtain the ER-807285 of 8.8g.The residuum of the reaction finished of purifying obtains 35.2g (productive rate is 74.5%) altogether in a similar fashion.
Two other experimental techniques are as described below.Its treatment stage different.The first relates to standard and finishes, and another kind of use anti-phase end (reverse quench).Use NH
4OH/MeOH/CH
2Cl
2Be to carry out TLC at 1: 9: 90 to analyze.Make the TLC plate develop the color to manifest initial feed and reaction product with the p-anisaldehyde spot.
Preparation 2: ER-819409-00 (995mg, 0.705mmol) is dissolved in CH
2Cl
2(7.8mL).At room temperature use 1~2 minute TFA (1.4mL) is added in this mixture.Then stirred reaction mixture 4 hours at room temperature.
After the stirring, use the ice bath reaction mixture, and with adding saturated NaHCO in 25 minutes
3The aqueous solution (16.0mL).The top temperature that records in N-process is~8 ℃, and medial temperature is 4 ℃.The mixture restir of gained 45 minutes is warming to room temperature with internal temperature from 4 ℃ during this period lentamente.Transfer to mixture in the separating funnel and add CH
2Cl
2(11.0mL).Layer was left standstill 35 minutes.Use CH
2Cl
2(5.0mL) extraction pH is 8~8.5 water layer.Merge organic layer and with 10mL pass through saturated brine solution and water are washed with the salt brine solution that 3: 1 ratio mixes to prepare.Layer was left standstill 20 minutes.Then organic layer is stored in the refrigerator (20 ℃) and spends the night.
Morning shifts out organic layer and is warmed to room temperature from refrigerator.Use Na
2SO
4Drying is filtered at the frit funnel, and is concentrated into drying.The oily matter of gained is dissolved in CH again
2Cl
2(8.0mL) and at tampon filter, to remove any salt resistates.The material of concentrate drying gained is to obtain colourless oily matter ER-807284-00 (727mg, mass recovery are 85%).Other CH
2Cl
2Extract the desirable material of the 99.0mg that provides extra, so that mass recovery is 96.8%.Needn't purifying.
The analytical data of ER-807284
●
1H-NMR(CDCl
3)δ0.85-0.95(m,12H),1.20-1.35(m,52H),1.45-1.65(m,8H),1.70-1.85(m,4H),2.25-2.65(bs,4H),2.28(t,J=7.6Hz,4H),3,20-3.27(m,2H),3.30-3.60(m,12H),3.98-4.22(m,10H),4.50-4.60(m,4H),4.95-5.05(m,2H),5.27(dd,J=0.9,10.5Hz,2H),5.38(dd,J=0.9,16.9Hz,2H),5.90-6.0(m,2H)。
● MS-APESI (M+H) C
61H
121N
4O
15P
2Calculated value: 1211.83 measured values: 1211.97.
Preparation 3: with CH
2Cl
2(22.3mL) install in the reactor of suitable specification.Add ER-819409-00 (2.85g, 2.01mmol) and be dissolved in CH
2Cl
2In.At room temperature with 1 minute adding TFA (4.0mL).At room temperature stirred reaction mixture is 4.5 hours.
Process: (anti-phase end): reaction mixture was transferred to the saturated NaHCO that is cooled to 0 ℃ by teflon catheter with 1~2 minute
3In the solution.Observe small intensification, exothermic maximum is~4 ℃.Use CH
2Cl
2(4 * 2.5mL) flushing reaction flasks also are added to washings in the solution.Remove refrigerating unit and with being warmed to room temperature in 45 minutes.Add again CH
2Cl
2(22mL), and with mixture transfer in the separating funnel.Before separating, mixture was left standstill 20 minutes.Use CH
2Cl
2(22mL) aqueous layer extracted and merge organic layer.Use salt brine solution, i.e. saturated brine/H
2O (than being 3: 1) (40mL) washs the organic layer that merges.The mixture of gained was left standstill 30 minutes, layer is separated.Layering.It is muddy that organic layer keeps.Organic layer is stored in-20 ℃ the refrigerator and spends the night.Then it is warmed to room temperature, uses Na
2SO
4Drying is filtered and concentrate drying at the frit funnel.Use again CH
2Cl
2(22mL) the reextraction salt brine solution is to reclaim other material.Proton and fluorine NMR spectrum show that these two groups of materials are all polluted by the tfa salt form.NaHCO
3The pH of layer analyze to show that pH is for~7 (not enough height (8~8.5) to obtain free alkali ER-807284-00 purely).Merge two groups and by organic substance is dissolved in CH obtained above
2Cl
2(50mL) come re-treatment.The solution that merges is transferred in three mouthfuls of round-bottomed flasks that are equipped with mechanical stirring device of 250mL.Add saturated NaHCO
3The aqueous solution (50mL) also at room temperature stirs the mixture 45 minutes of gained.With the substance transfer in the reactor in the separating funnel of 250mL.Use CH
2Cl
2(altogether 25mL) washes reactor.Standing mixt~1h also observes milk sap.Separate organic layer and water layer and use CH
2Cl
2(30mL) reextraction water layer.The organic layer that merges gained is with saturated brine (25mL) washing.Even after leaving standstill 1 hour, it is muddy that organic layer still keeps, and after this separates organic layer and water layer.Use Na2SO
4Dry organic layer filters at the frit funnel.Filtrate is muddy.Use CH
2Cl
2(25mL) reextraction salt solution.Behind similar drying step, will be from CH
2Cl
2The material of layer and other material merge.Organic filtrate of the merging of concentrate drying gained, (2 * 25mL) azeotropic are dissolved in CH again with MTBE
2Cl
2(10mL) and at the diatomite that is arranged in the 10mL syringe (3mL) filter beyond the Great Wall.The tip of described syringe is equipped with filtration unit to catch small-particle.Concentrate drying filtrate, the demonstration of NMR spectrum obtains diamines ER-807284-00 and does not contain tfa salt.Mass recovery surpasses 95%.By the TLC purification.Must repeat this processing producing free alkali purely, show to a certain degree degraded by TLC.Control pH can improve the method.
The preparation of embodiment 12:ER-807285-00
Preparation 1-EDC/HOBT: ER-807284-00 (1.0 equivalent) and anhydrous methylene chloride (8.41 weight) are installed in the inerted reactor of suitable specification.Then with 1-[3-(dimethylamino) propyl group]-3-ethyl carbodiimide (2 equivalent) is added in this reactor, adds subsequently I-hydroxybenzotriazole (0.18 equivalent).Then 3-oxo-tetradecanoic acid (2.2 equivalent) is joined in this reactor with three equal parts, stirred reaction mixture 10 minutes keeps T between each feeding in raw material
InnerAt 15~20 ℃.By TLC monitoring reaction, so that the ER-807284 completely consumed.When determining that (usually after 1 hour) is finished in reaction, water of productive use (5 weight) is added in the reactor.Stirred the mixture 20 minutes, then separated 20 minutes.Organic layer is put aside.Use in the above described manner twice of ethyl acetate (2 * 6 weight) reextraction water layer.Then merge all organic layers, add sodium sulfate (8 weight) and leave standstill 15 minutes to absorb moisture.Filter organism and use the ethyl acetate washing leaching cake, until obtain the negative findings of ER-807285.Vacuum (~50 holders, 28~35 ℃) concentrated filtrate obtains ER-807285.Utilize 3%~6%EtOH/CH
2Cl
2By this material of silica gel chromatography purifying.Merge the fraction of rich desired material and concentrated by rotary evaporation, and with IVAC pump (0.2 holder) drying 2 hours.The productive rate of colorless oil ER-807285 is 50%.
Preparation 2-EDC/DMF: ER-807284-00 (208mg, 0.172mmol) is dissolved in the DMF (2.1mL) in the suitable specification reactor, and adds EDC (263 mg, 1.37mmol).With mixture be cooled to 0 ℃ and with 30 seconds dropwise adding be dissolved in the 3-oxo tetradecanoic acid (166mg, 0.686mmol) of DMF (1.4mL).0 ℃ of lower reaction mixture that stirs gained 10 minutes, be warming to simultaneously room temperature.By TLC (7.5%MeOH/CH
2Cl
2: the p-anisaldehyde spot that is used for initial feed and product) monitor reaction.Lower to adding saturated NaHCO at 0 ℃ after~3 hours
3Solution (8.0mL), H
2The MTBE/ normal heptane (10mL) of O (4.0mL) and 1: 1 finishes reaction.Reaction mixture is transferred in the separating funnel.Then MTBE/ normal heptane flushing reactor with a small amount of 1: 1 merges with reaction mixture.Standing and reacting mixture 20~30 minutes separates organic layer and water layer afterwards.The cumulative volume of organic layer is~35mL.The TLC of water layer analyzes and shows a small amount of DMF.Do not need water layer is carried out reextraction.With salt solution (4.0mL) washing organic layer, then left standstill 15 minutes.Observe fast and separate, without milk sap.Separate organic layer and water layer, the evaporation drying organic layer obtains thick ER-807285-00.Use 3~6%EtOH/CH
2Cl
2Solvent system is at SiO
2Purification of crude ER-807285 on the post.Productive rate is 53%, (151mg ER-807285), and HPLC purity is 88%.
Preparation 3-HBTU/Hunig ' s alkali/DMF: ER-807284-00 (232mg, 0.191mmol) is dissolved in DMF (2.5mL).With reactor cooling to 0 ℃.Add HBTU (218mg, 0.574mmol) and 3-oxo tetradecanoic acid (139mg, 0.574mmol).Subsequently with dropwise adding Hunig ' s alkali (106uL, 0.612mmol) in 30 seconds.Reaction mixture was 0 ℃ of lower stirring 20 minutes and became emulsus after~10 minutes.Reaction mixture is warming to room temperature.Continue to stir above 4 hours.Because DMF is difficult with the TLC monitoring.Therefore, the reaction times can be shorter.With 1: 1 MTBE/ normal heptane (10mL) diluted reaction mixture, and transfer in the separating funnel of 60mL, and to use by the pH that makes the preparation of 1.0M citric acid (50uL) and saturated sodium-chloride (9.5mL) be that 3 the aqueous solution is processed.Form and separate out a large amount of salt, block funnel.Add water (5.0mL) so that salt dissolving, but be not separated after this, even also be like this afterwards little by little adding MTBE (at the most 15mL).Then add ethyl acetate until 10mL is separated to begin recovery.Make layer leave standstill~30 minutes to separate.It is 5 that the pH of water is adjusted to pH.The rare citric acid washing organic layer for preparing as mentioned above with 10mL again, obtaining pH is 3.Layering.Use saturated NaHCO
3Solution (2 * 5mL) washing organic layers.Separating obtained water layer and organic layer and evaporation drying organic layer.The productive rate of ER-807285 is 45% (143 mg), and HPLC purity is 91%.
The preparation of embodiment 13:E6020
Under argon gas stream, the ER807285 (1 equivalent) in degassed THF (1.57 weight) is installed in the inert containers of suitable size.Be added to (T in the reactor with the solution that four (triphenylphosphines) in tetrahydrofuran (THF) (2 weight) was closed palladium (0) (0.03 weight), triphenylphosphine (0.03 weight) and phenyl silane (0.07 weight) in 40 minutes
InnerUsually be increased to~40 to 45 ℃).Completely consumed by ER-804057 in TLC and the HPLC monitoring reaction.When determining that (usually after<10 minutes) are finished in reaction, by the ion-exchange chromatogram purification reaction mixture.For the more details about this purifying, referring to embodiment 14.
The purifying of embodiment 14:E6020
To contain the crude product mixture that four (triphenylphosphines) close 804057 free acids of palladium (0), triphenylphosphine and phenyl silane is loaded in the Source 30Q ion exchange column.Then, from 804057, elute unconjugated reactant with methyl alcohol/THF/ water (77.5/15/5).By the sodium salt (being E6020) with the sodium-acetate linear gradient wash-out 804057 from post that increases, described sodium-acetate begins with 0M and finishes with 0.05M.In this stratographic analysis process, remove impurity.
Optional secondarily purifiedly may wish.The E6020/ sodium-acetate ion exchanged soln that this stratographic analysis obtains from the chromatogram by the front begins.It directly is loaded on the C-4Kromasil post also with methyl alcohol such as buffer system such as degree such as grade/THF/ water/sodium-acetate (77.5/15/5/0.05M) wash-out.Merge the fraction that contains product, be used for Solid-Phase Extraction.
Then water dilutes pure E6020 solution with 50/50 and is loaded on the C-4Kromasil post.Then wash the linear gradient from water to the acetonitrile with water.This makes salt separate with pure E6020 with water.Then, with methyl alcohol eluted product from post.Obtain the solution of pure E6020 in methyl alcohol.25~30 ℃ and perfect vacuum indoor on rotatory evaporator concentrate drying.The vitreous product of freeze-drying or with the solution-treated of ethylacetate/acetonitrile forms white solid.Vacuum-drying obtains E6020.Embodiment 15: crystal ER-806158, (R)-1-(((R)-4,5-dihydro-2-phenyl
Azoles-4-yl) methoxyl group) last of the ten Heavenly stems-sign of 3-alcohol
A part of ER-806158 is dissolved in the warm toluene again, until all substances are all dissolved then cooling.This produces single crystal, the such single crystal of choice for use in this research.Oily (paratone oil) is being fixed on the glass fibre without the color lump crystalline substance of 0.14 * 0.14 * 0.10mm with size with the paratone of seldom measuring.
A. Single Crystal X-ray diffraction
Collect data with the diffractometer based on Bruker SMART APEX CCD (charge coupled device) that is provided in the Oxford Cryostream cyrogenic equipment that operates under the 193K.With the ω sweep measurement data of 0.3 ° of every frame 30 seconds, in order to collect hemisphere.Altogether collect 1271 frames, ultimate resolution is
When finishing, data gathering regathers 50 initial frames, with the monitoring decay.With SMART software (SMART V 5.625 (NT) Software for the CCD Detector System; Bruker Analytical X-ray Systems, Madison, WI (2001)) obtain unit cell parameters and carry out refine with SAINT based on all reflections that observe.(WI (2001) carries out data reduction for SAINT V 6.22 (NT) Software for the CCD Detector System Bruker Analytical X-ray Systems, Madison with the SAINT software of proofreading and correct Lp and decay.With SHELXS-97 program (Sheldrick, G. M.SHELXS-90, Program for the Solution of Crystal Structure, University of
Germany, 1990.) find the solution structure by direct method and by method of least squares to F
2Carry out refine, SHELXL-97, (Sheldrick, G. M.SHELXL-97, Program for theRefinement of CrystalStructure, University of
Germ any, 1997.), be incorporated among the SHELXTL-PC V 6.10 (SHELXTL 6.1 (PC-Version), Program library for Structure Solution and Molecular Graphics; Bruker Analytical X-ray Systems, Madison, WI (2000)).
In spacer P1 (#1), solve as shown in Figure 1 structure by vacant analysis of system.All non-hydrogen atoms of refine anisotropically.Find hydrogen and anisotropically refine by difference fourier method.The crystal that is used for diffraction investigation in data-gathering process does not show decomposition.Under 50% ellipsoid, draw all figure.Fig. 2 is the structure cell accumulation graph along a axle, and it is illustrated in the best figure of hydrogen bonded in the crystal, dotted line.
Table 1. crystal data and structure refinement
B. powder x-ray diffraction
Use quartz plate in 2 θ scopes at 5~70 ° under the conventional powdery diffractometry condition, also analyzing under the conditions shown in Table 2 with copper irradiation image data on the Scintag diffractometer.Do not use background correction.Fig. 3 represents the PXRD pattern of crystal ER-896158.The characteristic peak of the PXRD pattern of crystal ER-896158 is listed in table 3.
Table 2: measuring condition
X-ray diffractometer: Scintag
Target: Cu
Detector: lithium turbulence diode
Tube voltage: 40kV
Tube current: 30mA
Slit: DS 1.0, RS 0.3mm, SS 2mm pipe, 0.5m detector
Sweep velocity: 1 °/minute
Stepping I sampling: 0.02 "
Sweep limit: 5~70 "
Specimen holder: quartzy frame (25mm * 25mm)
Goniometer: θ-θ, fixing horizontal stand, goniometer
Wave filter: electronics
Monochromator: do not use
Table 3: powder x-ray diffraction characteristic peak (2 θ ± 0.22 θ)
6.9 | 20.2 | 25.2 | 41.6 |
11.9 | 20.5 | 25.4 | 48.9 |
13.6 | 21.7 | 26.5 | 55.2 |
19.5 | 23.3 | 27.4 | 58.6 |
19.7 | 24.2 | 34.4 |
C. the DSC of crystal ER-806158 characterizes.
Determine the solid-state feature of crystal ER-806158 by dsc (DSC, capillary technique).Use the crystal ER-806158 sample of 5.17000mg, under 50mL/ minute nitrogen purges, carry out the DSC operation what have an aluminum pan with 10 ℃ of/minute 2920DSCV2.5F calorimeters that are heated to 200 ℃.Fig. 4 is illustrated in nitrogen and exists lower crystal ER-806158 in 27 ℃ (initial temperatures) lower melting to absorb the thermogram of+29.2 cards/gram.Observe the melting that exothermic phenomenon is arranged first in the post bake process of sample, this shows that this ER-806158 can be stable at the most under 200 ℃ temperature in liquid phase.
D. the infrared spectra of crystal ER-806158
The FTIR absorption spectrum of crystal ER-806158 has recorded pure crystal powder.The IR absorption spectrum of crystal ER-806158 as shown in Figure 5.
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